peran nfkb dan breast cancer

Biomedicine & Pharmacotherapy 163 (2023) 114822
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
The role of NF-κB in breast cancer initiation, growth, metastasis, and

resistance to chemotherapy
Eluri Pavitra a, b, 1, Jyothsna Kancharla c, 1, Vivek Kumar Gupta a, Kiran Prasad d, Ju Yong Sung a,
Jigyeong Kim a, Mandava Bhuvan Tej e, Rino Choi b, f, Jeong-Hwan Lee b, f, Young-Kyu Han g,
Ganji Seeta Rama Raju g, *, LVKS Bhaskar d, *, Yun Suk Huh a, *
a
NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea
b
3D Convergence Center, Inha University, Incheon 22212, Republic of Korea
c
Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan 304022, India
d
Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur- 495009, Chhattisgarh, India
e
Department of Health care informatics, Sacred Heart University, 5151Park Avenue, Fair fields, CT06825, USA
f
Department of Materials Science and Engineering, Inha University, Incheon 22212, Republic of Korea
g
Department of Energy and Materials Engineering, Dongguk University-Seoul, Seoul 04620, Republic of Korea
A R T I C L E I N F O A B S T R A C T
Keywords: Breast cancer (BC) is the second most fatal disease and is the prime cause of cancer allied female deaths. BC is
Breast cancer caused by aberrant tumor suppressor genes and oncogenes regulated by transcription factors (TFs) like NF-κB.
NF-κB NF-κB is a pro-inflammatory TF that crucially alters the expressions of various genes associated with inflam
Chemoresistance
mation, cell progression, metastasis, and apoptosis and modulates a network of genes that underlie tumori
Apoptosis
Angiogenesis
genesis. Herein, we focus on NF-κB signaling pathways, its regulators, and the rationale for targeting NF-κB. This
Metastasis review also includes TFs that maintain NF-κB crosstalk and their roles in promoting angiogenesis and metastasis.
In addition, we discuss the importance of combination therapies, resistance to treatment, and potential novel
therapeutic strategies including nanomedicine that targets NF-κB.
Abbreviations: ABCG2, ATP binding cassette subfamily G member; ADAMTS18, A disintegrin and metalloproteinase with thrombospondin motifs; ATP, Adenosine
triphosphate; ATM, Ataxia telangiectasia mutated check point kinase; AKT, A serine/threonine protein kinase B (PKB); Bax, Bcl-2 associated X protein; Bcl-2, B-cell
lymphoma 2; BRCA1, Breast cancer gene; BRCP, Breast cancer resistant protein; CAIX, Carbonic anhydrase IX; CCL2, Chemokine (C-C motif) ligand 2; CCR7, C-C
motif chemokine receptor 7; CD40, Cluster of differentiation 40; CDK6, Cyclin-dependent kinase 6; CFTR, Cystic fibrosis transmembrane regulator; c-FLIP, Cellular
FLICE-inhibitory protein; COX2, Cyclooxygenase-2; CSC, Cancer stem cells; CXCL12, Chemokine (C-X-C motif) ligand 12; CYLD, Cylindromatosis; EGF, Epidermal
growth factor; EGFR, Epidermal growth factor receptor; EMT, Epithelial to mesenchymal transition; ER, Estrogen receptor; ERK, Extracellular signal-regulated ki
nase; FOXC1, Fork head box C1; GADD45B, Growth arrest and DNA-damage-inducible β; GPR120, G protein-coupled receptor 120; GPER, G protein-coupled estrogen
receptor 1; hTERT, Human telomerase reverse transcriptase; HIF-1α, Hypoxia inducible factor-1 α; IAP, Inhibitors of apoptosis protein; IFN, Interferon; IGF-1, Insulin-
like growth factor 1; IκB, Inhibitor of κ-B; IKK, IκB kinase; IL, Interleukin; iNOS, Inducible nitric oxide synthase; IRF-1, Interferon regulatory factor-1; JAG1, Jagged 1;
LPS, Lipopolysaccharide; LINC00472, Long intergenic non-protein coding RNA 472; MCSF, Macrophage colony stimulating factor; MDSC, Myeloid derived sup
pressor cells; MDR1, Multidrug resistance 1; MMP-2, Matrix metallopeptidase 2; MnSOD, Manganese dependent superoxide dismutase; MUC1, Mucin 1; NAP, Novel
angiogenic protein; NEMO, NF-κ-B essential modulator; NF-κB, Nuclear factor κ-B; PAK5, p21-activated kinase 5; P13K, Phosphatidylinositol-3-kinase; RANK, Re
ceptor activator of NF-κB; RIP, Receptor interacting protein; ROS, Reactive oxygen species; SERM, Selective estrogen receptor modulator; STAT, Signal transducer
and activator of transcription; SMYD2, SET and MYND domain-containing protein 2; TACE, Tumor necrosis α converting enzyme; TAM, Tumor associated macro
phage; TEL, Tumor associated leukocytes; TF, Transcription factor; TGF, Transcription growth factor; TLRs, Toll-like receptors; TNBC, Triple negative breast cancer;
TNFα, Tumor necrosis factor alpha; TNFRSF1A, Tumor necrosis factor receptor superfamily member 1A; TNFR1, Tumor necrosis factor receptor 1; TRAIL, Tumor
necrosis factor related apoptosis inducing ligand; TRAF2, TNF receptor associated factor 2; TRADD, TNFR1-associated death domain protein; uPA, Urokinase type
plasminogen activator; VCAM1, Vascular cell adhesion protein 1; VEGF, Vascular endothelial growth factor; XIAP, X-linked inhibitor of apoptosis; ZBTB7A, Zinc
finger and BTB domain containing 7A; ZEB, Zinc-finger E-box binding homeobox.
* Corresponding authors.
E-mail addresses: gseetaramaraju7@dongguk.edu (G.S.R. Raju), lvksbhaskar@gmail.com (L. Bhaskar), yunsuk.huh@inha.ac.kr (Y.S. Huh).
1
These authors both equally contributed to this work.
https://doi.org/10.1016/j.biopha.2023.114822
Received 17 January 2023; Received in revised form 27 April 2023; Accepted 30 April 2023
Available online 3 May 2023
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
E. Pavitra et al. Biomedicine & Pharmacotherapy 163 (2023) 114822
1. Introduction solid tumors results in the development of inflammatory TME [35,36].

The inflammatory response involved in the enhanced expression of
At present, cancer is the leading cause of death everywhere. The cytokine genes and the release of cytokines thereby activation of the
GLOBOCAN 2020 report found that 19.3 million new cases led to 9.9 canonical NF-κB signaling pathway resulting into the apoptosis of
million deaths [1]. Breast cancer (BC) is a typical form of the disease and transformed cells [37–39]. The leukocytes infiltrating result in the in
the second leading cause of global cancer-related mortality among crease of malignancies in breast epithelial cells and involves NF-κB
women [2–4]. The high mortality and morbidity rates of BC are due to signaling [40,41]. Therefore, it can be utilized as the potential marker
distant metastasis to brain, bone, liver, lungs and other organs [5]. In and therapeutic target for the prognosis and therapy of BC. Despite
2020, over 2.3 million BC cases (in both sexes) and 685,000 deaths were cytotoxic effect of drugs in eradicating tumors, they have some limita
recorded among women [6]. tions including side effects in different organs, because they are not
BC is most commonly encountered in female with a first-degree specific to cancer cells and target all proliferative and fast growing cells
relative diagnosed with the disease [7]. The chief risk factors associ including both normal and tumor cells [42]. The efficacy of endocrine
ated with BC are contraceptive pills (hormones), physical inactivity, lack therapy like chemotherapy, comes down in targeting metastatic BC due
of nutrition, obesity, hormone replacement therapy, alcohol consump to development of drug resistance. Because of the high incidence rate
tion, and smoking. Hereditary and genetic factors plays a vital role in the and limitations of conventional therapy for BC, it is important to look for
etiology of BC, and studies have revealed that mutations in the BRCA1 a new and effective target in cancer cells for targeted therapy. However,
and BRCA2 genes account for 5–10% of cases and that promoting the molecular mechanisms of NF-κB contribution towards the endocrine
breastfeeding and physical activity might reduce risk [8]. The devel therapy resistance are still not known. Although many reviews available
opment of treatment regimens like radio- and chemotherapy have on NF-κB and breast cancer, this review provides current understanding
improved prognosis and reduced mortality rates, but the onset of BC is of the NF-κB mediated signaling pathways during breast carcinogenesis
unpredictable due to aberrant genes that promote progression and and metastasis as well as pathways involved and therapeutic targets of
induce resistance to treatment. Aberrantly expressed transcription fac NF-κB. This article also elucidates NF-κB as a potential novel target for
tors (TF) attach to DNA loci and regulate gene expressions [9,10], and overcoming chemo-resistance.
oncogenic TFs enhance the expressions of oncogenic genes that activate
signaling cascades, mediate BC cell survival, and ultimately lead to 2. Methods of data collection
tumorigenesis [11]. The major dysregulated signaling pathways are the
Hedgehog (Hh), Wnt, Notch, and Nuclear factor κ-B (NF-κB) [12–15]. A bibliographic search of the scientific literature published till March
These pathways play a central role in the differentiation, proliferation, 2023 was carried out independently of different scientific databases and
and evasion of apoptosis. Studies have shown the importance of these search engines such as Scopus, Google Scholar, PubMed, and the li
pathways in the breast cancer tumor microenvironment (TME). The braries for original researchers. We also searched the results of various
breast cancer TME has high inflammation strengthened by the infil investigations on the effects of NF-κB towards chemotherapy resistance
trated immune cells, growth factors (GFs) and cytokines. Regulatory in BC. Adequate papers data indicating the results of clinical and pre
T-cells with negative immune feature associated with both ER-positive clinical studies were extracted independently using the standard method
and ER-negative breast tumors and confess an immunosuppressive of data extraction [43].
environment [13]. This characteristic feature has an importance in the
immune TME of breast cancer. 3. NF-κB mediated signaling pathways during the initiation,
NF-κB is a key TF that links inflammation with cancer. It has been development, and metastasis
demonstrated as being involved in the tumorigenesis in breast cancer
and resistance to the endocrine therapy. NF-κB plays an essential role in 3.1. CS and NCS pathways of NF-κB
the management of inflammation, proliferation, and survival of cell lines
[16–20]. NF-κB is a superfamily of TFs discovered in 1986 which in The NF-κB mediated CS and NCS pathways are summarized in Fig. 1.
cludes NF-κB 1 (p50) NF-κB (p52), ReIA (p65), ReIB, and C-ReI [21–23]. The CS pathway is initiated by IκB proteins (IκBα, IκBβ, IκBε, or IκBγ)
The N-terminal have ReI, which is responsible for the binding of specific and stimulated by TNF-α, which responds to UV radiation, cytokines,
DNA, while the C-terminal is responsible for binding with other TFs [24, growth factors, bacteria, and mitogens [44]. The pathway starts with the
25]. NF-κB is present in the cytoplasm as an inactive form by complexing interaction of TNFα with its receptor TNFR1, which recruits a sequential
with inhibitor subunits IΚB-α, -β and -ϒ [26–28]. The dissociation of protein including TRAF2, TRADD, and RIP. Among these adaptor pro
inhibitory subunits (IκB s) results in the activation and rapid trans teins the TRAF2 protein recruits the complex IKKα, IKKβ, and NEMO to
location of NF-κB heterodimer into the nucleus to bind with DNA [29]. bind with TNFR1 and it activates IKKβ, causing the phosphorylation of
The subunit p65 then displays its transcriptional activity and induces the IκBα [45,46]. The resulting ubiquitination of IκBα frees NF-κB (p50-p65
expressions of NF-κB target genes that inhibit apoptosis, and form a heterodimer) in cytoplasm and facilitates its migration to the nucleus,
network that regulates the cell cycle, and promotes cell invasiveness, where it attaches to NF-κB sites of DNA and induces the expressions of
inflammation, tumorigenesis, metastasis, and eventually causing resis IL-6 and also chemokines. On the other hand, the NCS pathway is
tance to radio- and chemotherapy. NF-κB is regulated by canonical initiated by growth factors, viruses, stress, and lipopolysaccharides.
signaling (CS) pathways (activated by IL-1, TNF-α, ROS and LPS) and CD40, a TNF receptor, participates in the activation of RelB/ NF-κB 2,
noncanonical signaling (NCS) pathways, which are activated by in which then recruits TRAF2-TRAF3, links c-IAP to NIK, and induces the
flammatory stimuli through IKKα [30]. However, the dysregulation of phosphorylation of NIK followed by degradation through c-IAP. NIK
NF-κB results in tumor evolvement, and thus activated NF-κB is detected activates IKKα and degrades p100, thus releasing p52 along with RelB,
in various cancers including BC [31]. Studies denote that NF-κB can which migrate towards the nucleus and induce the expressions of che
significantly upregulate the expressions of 60 related genes, including mokine genes [47,48]. Moreover, in BC cells, the activations of CD40
REL, RELA, GADD45B, TRAILR2, CD40, CCL2, IL15, CCND, CXCL12, and CD40L, mediated by an overactive oncogenic NF-κB signaling
VCAM1, COX2, and CXCL1 in inflammatory BC. Furthermore, COX2 pathway, result in neoplastic growth [49]. Interestingly, the expressions
along with CXCL1 are upregulated in metastatic BC [32]. The increased of the adaptor proteins, including cIAP1, TRAF2, FLIP, TRADD, and
expression of NF-κB genes results in tumor progression and metastasis XIAP, in BC cells can be attenuated by the TNF-α and IFN-γ-induced
[33,34]. activation of IRF-1 (interferon regulatory factor-1), which eventually
The role of NF-κB in tumor growth with reference to TME is very reduces nuclear NF-κB p65 levels in BC cells [50].
complex because of its various functions. The stimulation of NF-κB in During tumorigenesis many other pathways activate NF-κB, such as
2
the ATM kinase pathway, which causes NEMO ubiquitination under mutated p53 also contributes to the activations of EGFR, PDGF-1
genotoxic stress [51], the EGFR-dependent NF-κB transcription pathway (platelet derived growth factor 1), and NF-κB induces the expression
[52], H2O2-mediated NF-κB activation that induces the IκB phosphory of TGFβ, which together facilitate angiogenesis [62]. FOXC1 is a tran
lation by c-Src at Tyr42 [53], and the UV-facilitated NF-κB activation via scription factor and a reported prognostic biomarker of basal like BC and
casein kinase 2 independently of IKK [54]. The activations of these is overexpressed in many other cancers. It was shown that EGFR moti
pathways eventually result in the translocations of various NF-κB into vation upregulates the FOXC1 manifestation via PI3K/Akt, Ras/ERK,
the nucleus to activate its target genes. In the case of BC, it is initiated by and other pathways [63]. Furthermore, it was found that NF-κB acts as a
the steroidal hormone estrogens, as reflected by the number of estrogen pivotal mediatory by attached to the promoter region of FOXC1 and
receptors in BC cells [55]. However, BC development can change from controlling its expression via the EGF-dependent signaling pathway
being hormone-reliant and estrogen-attentive to a [64]. Hence, blocking the pathway of EGFR-NF-κB might offer a means
hormone-independent, invasive, and chemo-resistant phenotype, in of treating various cancers including BC.
which cancer progression is promoted by ER- tumor cells [56,57]. These
BC types include inflammatory BC types, such as Her2+ and ER- [58,59],
3.3. Cross talk among NF-κB and STAT3
which exhibit NF-κB overexpression and TNBC, which is highly meta
static and does not express Her2 or progesterone or estrogen receptors.
TFs couple to each other and bind to promoter sites essential for
TNBC results from a mutation in p53, that causes crosstalk among p53
transcription to mutually ensure their activities and binding to DNA,
and NF-κB [60]. NF-κB interacts with many distinct signaling pathways,
though later they may promote or inhibit each other. Research indicates
and the maintenance of crosstalk modulates its transcriptional activity.
that STAT3 is inappropriately stimulated in 70% of BC cells, especially
in TNBC, in which it contributes to pathogenesis [65]. The mechanism of
3.2. Cross talk among NF-κB and EGFR crosstalk among NF-κB and some other TFs during BC development,
proliferation, and metastasis is summarized in Fig. 2. STAT3 and NF-κB
Reports show that EGFR and its family members are widely circu regulate the functions of various genes responsible for chemokine and
lated in BC and are associated with the downstream NF-κB activation, cytokine production, anti-apoptosis, and cell cycle regulation [66,67].
predominantly in ER-BC cells [61]. When overexpressed, Her2 activates They remain transcriptionally active for minutes to 1 h under cytokine
NF-κB via activating PI3K/Akt signaling pathways in BC cells. Moreover, stimulation during which they constitutively drive gene expression.
Fig. 1. NF-κB mediated pathways. NF-κB operates via canonical and noncanonical signaling pathways. The canonical pathway starts with TNFα binding to its re
ceptor TNFR-1, which recruits TRADD, TRAF2, and RIP to form a complex. TRAF2 further recruits IKKα/IKKβ/NEMO complex. This activates IKKβ, which induces the
phosphorylation, ubiquitination, and proteasome degradation of IκBα. The liberated p65-p50 complex is then translocated to the nucleus, which binds to DNA and
activates NF-κB specific genes. On the other hand, the non-canonical pathway is activated by ligand binding to the CD40 receptor and the recruitments TRAF2 and
TRAF3 which facilitates c-IAP to NIK bonding, leading to the phosphorylation of NIK. Phosphorylated NIK then activates IKKα and partially degrades p100 to p52.
Thus, free p52-RelB then translocates to the nucleus and transcribes NF-κB targeted specific genes.
3
Fig. 2. Mechanism of crosstalk between NF-κB and transcription factors (A) STAT3, (B) HIF-1α, and (C) EFGR-dependent TGFβ and FOXC1. (a) Activated STAT3
mediates the acetylation of the p50/p65 heterodimer complex by p300 and increases its nuclear retention. In MDSCs, the RelB/P52 heterodimer complex regulates
STAT3 by the non-canonical pathway by upregulating IDO (indoleamine 2,3-dioxygenase) and causing immunosuppression and lymph node metastasis. In TNBC,
SMYD2 also activates STAT3, which results in the expressions of STAT3-specific genes. (b) Under hypoxic conditions, the p50/p65 heterodimer complex induces the
transcription of HIF-1α, which activates VEGF and iNOS genes that contribute to angiogenesis and chemoresistance. (c) Overexpressed EFGR activates via PI3K/Akt
and Mek/Erk pathway induces the expressions of p50/p65 heterodimer complex. The p50/p65 complex further expresses TGFβ, and FOXC1, contributing to
angiogenesis and chemoresistance.
These two transcription factors interact with each other in multiple SMYD2-TNFα-NF-κB-SMYD2 and SMYD2-IL-6-STAT3-SMYD2 with
situations, and these interactions control their functions and binding to epigenetic regulatory effects were found to promote TNBC. However,
their respective promoters. Moreover, STAT3-mediated acetylation of silencing SMYD2 or SMYD2 inhibitors (like AZ505) could reduce TNBC
NF-κB initiated by the acetyl transferase p300, promotes the modifica growth.
tion of RelA and enhances the nuclear retention of NF-κB, which pro
motes tumorigenesis. Similarly, NF-κB regulates STAT3 in BC via its
non-canonical pathway involving the MDSC-induced upregulation of 3.4. Cross talk among NF-κB and HIF
indoleamine 2,3-dioxygenase [68]. MDSCs are immunosuppressors and
induce lymph node metastasis in BC. In the CSC (cancer stem cell) of BC, Hypoxia inhibits tumor cell proliferation, but tumor cells develop
STAT3 allies with CD44 and NF-κB to activate hTERT, whose expression resistance against drugs under hypoxic conditions and become pheno
is correlated with poor prognosis [62,69,70]. There are certain genes typically metastatic. This process is maintained by inducible factors like
that promote the simultaneous activations of both STAT3 and NF-κB. For HIF-1α (hypoxia inducible factor 1) and CAIX (carbonic anhydrase IX)
instance, TNFRSF1A is a STAT3-dependent gene induced by cytokine and modulates target genes like VEGF and iNOS [73] that promote ox
activation, and also TNFRSF1A is a receptor for TNF-α, that induces ygen production or allow the cells to adapt to hypoxia metabolically
NF-κB activation when it binds with TNF-α. Thus, TNFRSF1A belongs to [74]. On the other hand, HIF-1α can also respond to certain factors,
STAT3 target gene which controls NF-κB, promotes TNBC, and is a po including ROS, IGF-1, and TNF-α, under normoxic conditions. NF-κB
tential biomarker [71]. Moreover, targeting genes that functions as a (the downstream target of TNF-α) controls HIF-1α transcription and
node between two oncogenic pathways could provide a novel thera specifically binds to the HIF-1α promoter site, which also contains p65
peutic strategy. Li et al. [72] determined that SMYD2 can methylate p53 binding sites for the guidance of oxidative stress and inflammation
and thus prevent it from tying to its facilitators and inhibit apoptosis. induced tumor cell progression [75,76]. Thus, a crosstalk exists among
Moreover, SMYD2 was found to promote TNBC through the methylation HIF-1α and NF-κB. Similarly, NF-κB activation via IκB phosphorylation
of its non-histone substrates, including STAT3 & NF-κB, to regulate the is allied with mRNA and protein levels of HIF-1α [77,78]. Crosstalk
expressions of genes contributing to tumor progression. Furthermore, between these two TFs, regulates and moderates the transcriptions of
synergistic cross-talk was identified between SMYD2, NF-κB and STAT3 various genes with crucial roles in cellular processes, like cell pro
in TNBC cells, and positive response loops between graming to adapt to hypoxic conditions and promote EMT. Proteins, like
MUC1 are regulated via both NF-κB and HIF-1α. MUC1 is a glycoprotein
4
involved in cell signaling and apoptosis inhibition [79], and its expres 4. Role of NF-κB in different cellular functions
sion in BC cells was reported to degrade IκBα (the inhibitor of NF-κB),
and thus to promote the nuclear translocation of NF-κB, induce cell 4.1. NF-κB as an anti-apoptotic
survival, and inhibit apoptosis. Furthermore, in MUC1+ BC cells, NF-κB
was overexpressed and p53 inactivated [80], and HIF-1α modulated NF-κB regulates apoptosis but its role is tricky. The effect of NF-κB on
VEGF expression and allowed cells to adapt to hypoxic conditions [80]. apoptosis is determined by the balance between genes which promotes
Thus, it appears that HIF-1α and NF-κB are initiated in MUC+ BC cells cell survival and apoptosis [86]. NF-κB expression is widely observed
[81]. Also, the molecular evidence indicates NF-κB is essential for IL-6 during mammary gland development. Moreover TRAIL, which encour
expression in BC cell lines, and the activation of IL-6 stimulates its ages apoptosis, is upregulated when NF-κB is inhibited in BC cells [87].
downstream signaling transducers including HIF-1α and STAT3 [82]. However, during tumorigenesis, TRAIL expression reflects drug resis
Thus, the interaction among NF-κB with STAT3 and the potentiation of tance. Woo et al. [88] observed that YM155, a survivin inhibitor, sen
tumor progression by HIF-1α suggests targeting IL-6 or NF-κB might sitizes TRAIL and induces apoptosis. The collective treatment by YM155
inhibit the tumor progression. Moreover, recent studies revealed that and TRAIL enhanced the apoptosis of several cancer cells, including
GPER (G protein-coupled estrogen receptor) actively inhibits the ex renal, breast, and glioma cancer cells. Subsequently, YM155 was found
pressions of IL-6 and VEGF. However, during tumorigenesis GPER loses to potentiate TRAIL-mediated apoptosis through cathepsin S by down
its tumor suppressive activity. Liang et al. [83] showed that combining regulating the actions of Mcl-1, c-FLIP, and NF-κB. Furthermore, com
G-1 agonist to GPER potentiates the GPER-mediated inhibition of bined treatment with Ebselen and γ-radiation upregulated the actions of
IL-6/NF-κB, further inactivating HIF-1α and STAT3 and inhibiting TRAIL at its mRNA level and downregulated NF-κB protein levels, and
angiogenesis and metastasis in TNBC. IL-1β was also found to upregulate significant reductions were detected in TNF-α, TGF-β, IL-2, and INF-γ
the countenance of HIF-1α in various cancers through NF-κB dependent [89]. Earlier studies reported that Bcl-2 overexpression in human BC
pathways [84]. IL-1β enhanced cell migration and proliferation under cells had an anti-apoptotic effect and enhanced NF-κB activity-related
hypoxic conditions in MDAMB231 cells by upregulating NF-κB, HIF-1α, metastatic potential [90,91]. The Bcl-2 family, which is made of
and CXCL8, but inhibiting HIF-1α did not suppress IL-1β induced tumor anti-apoptotic proteins, that bind to Bax and prevent it from oligome
migration because HIF-1α action was preserved via the activation of rizing and penetrating the mitochondrial membrane to prompt the ac
NF-κB [85]. Thus, the novel therapeutic strategies should be developed tivities of caspase 3 by inducing cytochrome c release, which further
to target inflammatory components differentially in the microenviron inhibits apoptosis. In BC cells, Bcl-2 is overexpressed and plays very
ment of BC. important role in the progress of chemoresistance, and Bcl-2 is activated
Fig. 3. NF-κB-mediated antiapoptotic pathways and the development and regulation of BC. NF-κB activation leads expression of various anti-apoptotic and cell
survival proteins. Apoptosis is controlled by these proteins at various levels. These are A) Fas-mediated extrinsic apoptotic pathways are downregulated by c-FLIP via
inhibiting activation of caspase-8. B) c-IAP1/2 regulates TNF-α induced apoptotic signals by suppressing the activation of caspase-8. C) Upregulation of anti-apoptotic
proteins like Bcl-2, Bcl-xL, and Mcl-1 inhibits BAX/BAK thus preventing cytochrome C release from mitochondria and subsequent apoptosome formation. D) Caspase-
9 activation is downregulated by survivin-XIAP complex or phosphorylated survivin. Survivin-XIAP complex also prevents caspase 3 activation. Hence apoptosis is
downregulated. Also, survivin binds to Aurora kinase B and INCENP (inner centromere protein) forming a complex that regulates cell mitosis. E) Cyclin-D1-CDK4/6
complex phosphorylates Rb (retinoblastoma) protein releasing free activated E2F which binds to DNA activating S-phase genes, thus causing cell cycle progression.
5
by NF-κB [92]. Ren et al. [93] postulated that chrysophanol might interactions between cyclins and NF-κB, this topic remains controver
inhibit BC cell progression by suppressing the phosphorylation of NF-κB sial. Therefore, future research is necessary to establish the role of
and the corresponding downstream pathways, such as the cyclin D1 and cyclins in BC cell cycle development and NF-κB activation.
Bcl-2 pathways. These findings show NF-κB plays an important role in During tumorigenesis, aberrant activity of PI3K induces the activa
BC development and the inhibition of apoptosis. NF-κB-mediated tion of AKT and the expression of p65, and eventually promotes the
anti-apoptotic pathways during BC development are summarized in expressions of EMT regulatory proteins like N-cadherin and vimentin
Fig. 3. and downregulates E-cadherin causing metastasis via EMT. Twist1 is a
helix-loop-helix that contains TFs, and mutated Twist1 has been etio
4.2. Function of NF-κB: A cell cycle regulator and metastatic promoter logically associated with various diseases like cancer and Saethre-
Chotzen syndrome. Furthermore, Twist1 activates STAT3, HIF-1α, NF-
Cyclins and CDK play a central role in governing the mammalian cell κB and integrin-linked kinase in several cancers like liver, breast, and
cycle. The cyclin D1 and Cyclin D, and CDK4 and CDK6 are overex prostate, and also induces EMT by upregulating E-cadherin thus pro
pressed in BC. Guttridge et al. [94] determined the essence of the as moting metastasis, invasion, and treatment resistance in cancer cells
sociation between NF-κB and cyclin D, whereby NF-κB regulates growth [99]. In addition, as discussed earlier, TNF-α promotes EMT and can
and progression via cyclin D1 (Fig. 4). It was also shown that RANK induce cancer cell stemness by upregulating Twist1 in breast epithelial
(receptor activator of NF-κB) induced the NF-κB activation in mammary and BC cells, as demonstrated by Chia et al. [100]. Although the role of
epithelial cells, where cyclin D1 appearance is significantly upregulated NF-κB in the promotion of EMT has been elucidated, the role played by
[95]. Recently, Zhang et al. [96] evaluated the relation between PAK5 TNF-α remains unknown. Findings suggest that NF-κB is operated by
(P21cdc42/rac1 -activated kinase 5) and p65 in BC tissue, and Wang et al. TNF-α in BC cell lines, and this results in the upregulation of Twist1 and
[97] reported how to inhibit cell cycle arrest at G0/G1 phase and nuclear migration of p65 via the activation of IKKβ through the CS
upregulated cyclin D1 in BC cells. They also characterized that PAK pathway. This further promotes the expression of the Twist1 gene,
induces the phosphorylation of p65 and promotes the nuclear migration which suggests that the Twist1 promoter region is essential for medi
of NF-κB, which eventually attaches to the promoter region of cyclin D1. ating EMT-induced inflammation and metastasis. Similarly, CFTR
These observations show PAK upregulation increases cyclin D1 expres (cystic fibrosis transmembrane conductance regulator), which is widely
sion via NF-κB in vitro and in vivo and that cell cycle movement is described in epithelial cells, possesses a Cl(-) and HCO3(-) conduction
governed by CDKs and their inhibitors as coordinated by cyclins. Shen anion channel, and inhibits invasion, migration, and metastasis by
et al. [98] proposed that NF-κB upregulates CDKs and cyclin D1 and downregulating EMT markers and thus suppressing EMT [101,102]. In
determined that simvastatin (an antitumor drug) restricts the cell cycle addition, CFTR can also impede NF-κB, which triggers uPA (urokinase
progress and encourages apoptosis via downregulating the expression of type plasminogen activator) and plays a vital role in governing EMT.
CDKs, MMP-2, and cyclin D1 via inhibiting the NF-κB activation. However, the expression of CFTR is downregulated in BC samples,
Although multiple experimental models have been used to investigate which results in aberrant NF-κB activity and is allied with deficient
Fig. 4. NF-κB and its downstream pathways in breast cancer progression and metastasis. TNF-α activated p50/p65 complex upregulates MMP2, cyclin D, and D1. The
RANKL binds to its receptor, activating TRAF 6 which activates Table1/Tak1 and NIK. The Table1/Tak1 complex activates the p50/p65 dimer and NIK activates
RelB/p52 dimer via canonical and non-canonical pathways respectively. The activated p50/p65 and RelB/p52 dimer upregulate the expression of cyclin D1. These
cyclins maintain the progression of cell cycle. EFGR-mediated PI3K/Akt and Mek/Erk pathways activate the transcriptions of the N-cadherin, vimentin, Twist1, TGF-
β, MMP-2/9, and VEGF genes. These contribute to EMT (epithelial-to-mesenchymal transition) and distant metastasis.
6
prognosis [103]. Moreover, NF-κB activation also induces Ras and TGFβ this study, the exposure of BC cells to estradiol significantly regulated
dependent EMT and regulates EMT phenotype by binding to E-cadherin CCL2 synthesis in estrogen-positive BC cells and upregulated the TWIST
repressor promoter and ZEB-1/2 [104,105]. expression via activating the P3K/AKT/NF-κB pathway. Thus, TWIST
MiR655 is an oncogenic miRNA that elevates the production of stem- was found to promote EMT, induce angiogenesis and contribute to
like cells, and significantly upregulates COX-2 expression in human BC metastasis in BC [127]. Similarly, progesterone, which targets receptors
cells in an EP4-dependent manner[106]. Thus, the ectopic over in mammary epithelial cells, also induces cell proliferation in a cyclin
expression of miR655 is dependent on EP4 activity and downstream 1-dependent manner [128]. Progesterone also promotes the synthesis
pathways of EP4 along with NF-κB and PI3K/AKT/ ERK pathways that and release of RANKL from progesterone-positive luminal cells, which
eventually promote progression and EMT in BC cells [107]. Recently, a interacts with and expands RANK receptors in the progesterone-negative
novel biomarker ZBTB7A (zinc finger and BTB domain containing 7A) luminal cells of mouse mammary glands by activating NF-κB [129–131].
was identified and detected its involvment in the development of various Thus, this pathway induces the transcriptions of various genes that are
cancers including BC. A new insight also revealed that ZBTB7A is implicated in BC cell proliferations.
expressed actively in BC metastasis and prmotes EMT. Additionally, MT-2A (Metallothionein-2A) is another protein often detected in
ZBTB7A activity was regulated by NF-κB p65 in BC cells, indicating that invasive BC tumors. MT-2A expression upregulated MMP-9 and AP-1
ZBTB7A is involved in EMT promotion and that metastasis was induced proteins and the transcription of NF-κB. Furthermore, the silencing of
via the NF-κB pathway [108]. Lymph node metastasis is the most MT-2A featured to prevent the invasiveness of BC cells. Hence, MT-2A is
common metastatic complication in BC, and the expressions of surface a promising therapeutic marker for regulating the activation of NF-κB
markers CD44high/CD24-/low are widely considered to be responsible for [132]. Additionally, Farina et al. [133] determined that AP-1, SP1, and
metastasis in BC [109–111]. Furthermore, it has been reported that the NF-κB play crucial roles in augmenting MMP-9 through Trx-1 (thio
activations of TALs (tumor associated leukocytes) have an important redoxin 1), where Trx-1 is known as a redox protein usually detected in
role in mediating metastasis [112]. El-Ghonaimy et al. [113] performed BC cells. Trx-1 dysregulates the balance among MMP-9 and TIMP-1, and
cytokine profiling using an antibody array on leukocytes isolated from is involved in the invasiveness of BC cells and strengthens MMP-9
tumor microenvironment and on positive and negative lymph nodes expression at the transcription level by altering the DNA bound NF-κB
obtained surgically from a BC patient and detected CD45+ cell infiltra activity and mediating the transcription of MMP. Thus, the overex
tion in positive but not in negative lymph nodes. Additionally, they pressed Trx-1 and NF-κB may be used as druggable targets that enable
observed improved NF-κB /p65 signaling and increased secretions of the regulation of MMP-9 in BC.
IL-1α, TNF-β, IL-5, and IL-3 in the TALs of positive lymph nodes isolated TNFα is a pro-inflammatory cytokine that enables tumor and meta
from BC samples. Moreover, the upregulation of of CCR7 (C-C chemo static progression by promoting angiogenesis and EMT. Rivas et al.
kine receptor 7) has been discovered in MCF-7 cells and found to play a [134] found that TNF-α is mitogenic and can promote the over
crucial part in metastasis. expression of ErbB2 in BC cells, which causes its phosphorylation at
The oncogene ErbB2 is overexpressed in human BC, and recent Tyr877 in mouse and human BC cell lines. Additionally, it can induce the
research has determined that ErbB2 can induce tumorigenesis in Akt and NF-κB activation, whereas knock-down or prevention of ErbB2
immunocompetent mouse that showed NF-κB activation and thus by siRNA or AG825 (an EGFR inhibitor), respectively, blocks the acti
boosted VEGF expression and angiogenesis. Under hypoxic conditions, vation of TNF-α, and thus regulates the NF-κB expression. Recently,
VEGF levels are increased, and binds to integrin αvβ5, which is actively Yvonne et al. [135] demonstrated that, WBP2 (WW-domain-binding
found in newly developed blood vessels and facilitates interactions be protein 2) potentiates TNF-α induced cell migration and invasion by
tween extracellular matrix and endothelial cells. Besides, NF-κB in activating NF-κB in TNBC cells. Here, WBP2 elevates ubiquitin-mediated
tumor cells cannot regulate the integrin expression that mediates proteasomal degradation of IκBα (an upstream inhibitor of NF-κB) by
angiogenesis. Moreover, the prevention of NF-κB may stimulate the enhancing mRNA stability of BTRC (beta-transducin repeat-containing
resistant ErbB2 cells to anti-ErbB2 monoclonal antibodies [114]. Nataraj E3 ubiquitin protein ligase) to promote TNBC cells aggressiveness.
et al. [115] identified crosstalk among VEGF and NAP (novel angiogenic Likewise, Meiling et al. [136] found that CECR2 (cat eye syndrome
protein), which promotes the expressions of VEGF and Flt-1. They found chromosome region candidate 2) plays a key role as an epigenetic driver
that tube formation of NAP is connected with invasion and migration. in promoting BC metastasis and thus by targeting CECR2 bromodomain,
Also, they determined the existence of NAP in the tumor cytosol using the expression of prometastasis genes and NF-κB-mediated immune
anti-NAP-mAb. Furthermore, NAP promoted the NF-κB activation in BC suppression can be reduced at the metastatic sites of BC. In another
cells through activating the JNK and MAPK pathways, as NAP is phos study, Rahma et al. [137] demonstrated that, the NF-κB transcriptional
phorylated by VEGF and has a vital role in motivating its downstream activity and its phosphorylation was inhibited by Russelioside A which
target NF-κB. Thus, VEGF is an angiogenic factor that plays an important leads to the reduced metastatic capacity in 4T1 BC cells. These obser
role in inducing angiogenesis. vations indicate that NF-κB portrayed a vital role in inducing angio
Tumor-associated macrophages (TAMs) observed in the microenvi genesis and promoting metastasis in BC.
ronment of the tumor are generally activated by MCSF (macrophage
colony stimulating factor) and CCL2 (chemokine ligand 2 with C-C 4.3. NF-κB and tumor suppressor genes
motifs) [116,117]. A vital role was played by TAM in carcinogenesis via
promoting cancer progression and angiogenesis and secreting angio Tumorigenesis results from aberrant intracellular signaling resulting
genic factors like VEGF [118–120]. In tumor cells, the activities of MCSF in the NF-κB activation, which rescues tumor cells from apoptosis and
& CCL2 mediate NF-κB activation in macrophages, which increases elevates uncontrolled mammary epithelial cell growth. BRCA1 is one of
VEGF release [121]. It has also been shown that TACE (tumor necrosis the tumor suppressor gene that responsible for hereditary BC protein
alpha converting enzyme) facilitates the release of soluble factors like which aids to the homology-directed DNA repair of double-strand breaks
MCSF [122], EGFR [123], and TNF [124] from the ectodomain, and that [138]. Besides, its absence due to mutation or knock-down in mammary
the expressions of these factors in BC cells are associated with poor cells leads to replication fork stalling resulting in genetic instability and
survival of patient [125]. Rego et al. [126] detected an interaction of double-strand breaks [139]. Hence, the absence of BRCA1 results in the
TACE shed MCSF and CCL2 in vitro in mammary cell lines and in vivo stimulation of ATM (ataxia telangiectasia mutated check point kinase)
using BALB mice and showed tube formation by endothelial cell. These and H2AX phosphorylation, which further contributes to genomic
findings indicate TACE stimulates macrophage pro-angiogenic activity instability resulting from DNA damage. During this process, ATM in
via NF-κB and VEGF expression. Recently, the CCL2-CCR2 axis was duces the recruitment of various proteins including NF-κB, via NEMO
anticipated as a novel therapeutic strategy in hormone-dependent BC. In phosphorylation (the inhibitor of IκB kinase) for DNA damage repair
7
[140–142]. Thus, activated NF-κB promotes anti-apoptotic cascades. In cascade when RGD-integrin is intact with L1CAM molecule enhancing
addition, when activated, NF-κB utilizes various other cascades to IL-1β production in TGF-β1 treated cells, and were the first to report a
enhance recombination by stimulating the interaction of CtIP-BRCA1 L1CAM dependent signaling cascade involving the ligation of L1CAM by
complex [143]. Likewise, the NF-κB activated during DNA damage integrin and eventual promotion of the NF-κB activation. Kendellen
and replication stress induces the acetylation and phosphorylation of et al. [160] found that NF-κB is actively expressed in tumor-initiating
p53 [144]. This posttranslational modification stabilizes p53 and in cells endowed with the potential to self-renewal in various cancers
duces the activation of various genes which monitor the cell cycle, through both CS and NCS pathways, as was observed in derived
progression, and apoptosis [144–146]. However, when mutated p53 basal-like and claudin-low subtypes of BC cell lines. NF-κB was also
becomes oncogenic and positively regulates the pro-tumorigenic activity detected to elevate EMT and upregulate the expressions of IL-6 and IL-1β
of NF-κB. As evidenced by earlier studies, absolute crosstalk occurs in tumor-initiating BC cell lines. Furthermore, CSC activation by the
among p53 and NF-κB, and p53 behaves as a license element for the Notch-1 pathway in BC cells was discovered to be NF-κB dependent
activities of NF-κB and its target genes [147–149]. The interaction de [161]. CSCs such as fibroblasts, macrophages, and non-CSC associated
pends on the chromatin attached p53/NF-κB p65 complex under stress with NF-κB activation via Notch-1 signaling are associated with the
and cytokine-dependent conditions. Moreover, HDACs (histone deace production of JAG1 (jagged 1), a Notch pathway ligand, that plays an
tylases) are connected with the epigenetic modifications of p53 and important role in self-renewal of CSCs in basal type BC cells. Besides, the
NF-κB [147,150]. HDAC inhibitors are widely used as anti-tumor agents NF-κB dependent paracrine activation of Notch signalling to induce
and can induce cross talk among p53 and NF-κB and thus block the JAG1 expression was detected during B-cell activation [162]. Further
activity by class I HDAC along with the chemotherapeutic agents like more, the Notch-1 signalling pathway activates the NF-κB and promotes
hydroxyurea [151]. Weisz et al. [152] also determined that mutated p53 the upregulations of its downstream target genes like VEGF, cyclin D1,
amplifies the activation of NF-κB via the TNF-α induced upregulation of MMP-2/9, Bcl-xL and Survivin, which promote BC progression [163].
the NF-κB 2 gene. Receptors also have an important role in facilitating the expressions
ADAMTS (a disintegrin and metalloproteinase with thrombospondin of transcription factors. TLRs (toll like receptors) promote BC progres
motifs) forms catalytically active oligomers that are also dysregulated in sion and are related to poor prognosis [164,165]. Stimulation of TLRs in
many cancer types. ADAMTS18 is one of the most often hyper BC drive tumor cells towards the CSC phenotype, and is boosted by the
methylated tumor suppressor gene in several cancers, including BC, and activations of the NF-κB and β-catenin but not by NF-κB alone [166].
this hypermethylation causes ADAMTS18 to lose its tumor-suppressing RIP2 (receptor-interacting protein kinase 2) is a TNF receptor that
function [153]. However, demethylation restores the activity of directly activates NF-κB, JNK, MAPK, and ERK [167,168] and has a vital
ADAMTS18 in BC cells. Furthermore, the ectopic behavior of role in developing immunity and inflammation [169–171]. Moreover,
ADAMTS18 in BC cell lines suppresses tumor cell migration, invasion, the TNF receptor is overexpressed in triple negative BC (ER, PR, and
and metastasis by deregulating NF-κB and AKT signaling [154]. These Her2) which is correlated with poor survival, and has been demon
findings could result in the novel therapeutic strategies for BC. strated to facilitate metastasis, knock-down RIP2, and sensitize BC cells.
Thus this receptor could be used as a prognostic marker for BC man
4.4. NF-κB -mediated signaling pathways and carcinogenesis agement [172]. Since NF-κB is the prime source for the development of
resistance to endocrine therapy, inhibiting ER expression and NF-κB
Among the NF-κB subunits, p100 has been widely detected at activity might desensitize cells to ER antagonists, which suggests the
elevated levels in BC tissues, and acts as a precursor for NF-κB affiliated possibility of combinational therapy with anti-inflammatory drugs like
proteins in cytoplasm. Previous studies have reported that ~90% of BCs dimethyl fumarate.
are caused by dysregulated expressions of the subunits p50, p52, and c-
Rel [155]. However, very limited information is acknowledged about 5. Role of NF-κB in the resistance to therapy
the activity of RelB in BC cells. Mineva et al. [156] established that
ectopic c-Rel induces the expression of RelB and an inverse relationship 5.1. Role of NF-κB in BC resistance to chemotherapy
among RelB and ERα expressions in BC cells. They determined that the
activation of RelB improved the survival rate of BC cells by upregulating The activation of NF-κB potentiates the transcriptions of various pro-
Bcl-2, survivin, and MnSOD (manganese-dependent superoxide dis survival factors, including cyclin D1, Bcl-xL, and IAPs, and thus pro
mutase) and promoting resistance to γ-radiation and doxorubicin in ERα motes anti-apoptotic signalling in BC [173–175]. This activation even
negative breast cells. Moreover, they also observed that 1,25(OH)2 D3 tually contributes to resistance against radio-, chemo-, and endocrine
reduces the activation of RelB and BC cell survival. IκBα is the most therapies [176].
commonly studied inhibitor of NF-κB which also regulates the activation About 75% of BC cases are attributed to ER, which is commonly used
of NF-κB. However, its dysregulation causes NF-κB overactivation in as a biomarker of disease progression as well as for guiding endocrine
various cancers, including BC. IκB kinase ε (IκKε; another IκK family therapies based on SERM (a selective estrogen receptor modulator),
member) activates the NF-κB and interferon by the NCS pathway. IKKε is tamoxifen,and aromatase inhibitors. The interaction between NF-κB and
a ser/thr kinase that portrays an essential role towards viral ERα shows an inverse correlation [177–179] in case of expression and a
infection-induced inflammation and a breast oncogene responsible for reciprocal inhibition is detected between them as it supress inflamma
30% of BC cases when amplified and overexpressed [157]. CYLD is a tion and blocks the nuclear migration of NF-κB and its bond with DNA.
tumor suppressor which regulates the activity of NF-κB. However, the NF-κB activation causes tumor progression mostly in ER- tumors
overexpression of IKKε deactivates CYLD by phosphorylating it at [180–182] and not in ER+ tumors, which tend to respond to tamoxifen.
ser418, which leads to NF-κB activation and tumorigenesis. Similarly, However, 40–50% of ER+ tumors do not respond to the therapy because
IKKε was also reported to phosphorylate TRAF factor at ser11, which they develop resistance to tamoxifen and express NF-κB at high levels
induces the ubiquination of TRAF at lys63 required for the activation of [183,184]. Thus, the endocrine therapy that should suppress ER and
NF-κB, and has been correlated with primary breast carcinoma [158]. inhibit NF-κB, however leads to the NF-κB activation as a marker of
Previous studies have determined NF-κB is expressed in BC cells and developing endocrine resistance. In tumor cells, the endocrine resistance
that various oncoproteins mediate its expression. For instance, dysre induces an assertive phenotype involving various genes expression
gulation of L1CAM (L1 cell adhesion molecule) is associated with associated with EMT, stemness, and disease recurrence [177]. Further
insufficient prognosis in various cancers, including ovarian cancer, more, the expressions of IAP, Bcl-xL, and resistance proteins (BRCP and
PDAC, and BC. Kiefel et al. [159] reported that L1CAM also mediates the ABCG2) are widely detected markers of resistance [185]. Moreover, the
signaling of NF-κB by activating the integrin-FAK-Src-Akt signaling presence of the BRCP polymorphism can serve as a prognostic aspect for
8
the development of tamoxifen resistance and NF-κB activation. that RIP2 also offers resistance to paclitaxel and apoptosis caused by
LINC00472 (long intergenic non-coding RNA) in BC inhibits the pro ceramide via NF-κB pathway activation in TNBC cells. Moreover,
gression of tumor, and its lower expression is associated with low sur blocking RIP2 expression could repress NF-κB and sensitized tumor cells
vival [186,187]. It was found that ERα promotes the expression of to paclitaxel [196]. As regards immunotherapy, trastuzumab treatment
LINC00472 and suppresses the activation of NF-κB. Upon tamoxifen of PTEN-silenced BC cells results in the advancement of CSC populations
treatment, LINC00472 expression was reduced, coupled with the upre via the activation of a NF-κB-IL-6 feedback loop [197]. In addition,
gulation of NF-κB expression in ER+ breast tumor as a marker of certain drugs including platinum compounds, such as paclitaxel, and
developing resistance [188]. vinca alkaloids, which are involved in disrupting microtubule formation
Moreover, in ER- BC cells, low LINC00472 expression was detected and can activate NF-κB induced treatment resistance [198]. CSCs have
and correlated with poor prognosis. Thus, continuous tamoxifen the ability to develop resistance and are prone to recurrence [199–201],
administration might prevent the limitation of NF-κB activation by whereas NF-κB-IL-6 signalling can promote self-renewal and chemo
LINC00472. However, the use of combined regimen might potentiate resistance following chemotherapy [202]. Saha et al. [203] exposed
endocrine therapy by inhibiting ER as well NF-κB expression. Kastrati breast CSC cells to aspirin to disturb the NF-κB and IL-6 signalling
et al. [189] developed a hybrid drug with reduced side effects and an pathways and prevent the nuclear translocation. Aspirin treatment
efficient pharmacokinetic profile capable of targeting multiple sites. sensitized CSCs to combinatorial treatments with 5-FU, cyclophospha
They used the raloxifene (an SERM) as an ER inhibitor along with mide, and doxorubicin. Thus, it appears combining antagonists with
anti-inflammatory drug fumarate to inhibit the NF-κB pathway. Results conventional combinational therapy might provide a means of
showed raloxifene-fumarate combinatorial treatments offer a potential improving recurrence-free survival in BC. A list of the drugs tested for
means of improving the anti-inflammatory effects of ER-targeted BC clinical trials is provided in Table 1.
therapy.
5.2. Role of NF-κB in BC resistance to radiotherapy
5.1.1. NF-κB targeting to overcome chemoresistance in BC
Chemotherapy is an adjuvant therapy of cancer, however chemo Radiation is another conventional therapy used for cancer treatment.
resistance and recurrence are the most common obstacles to successful As discussed, resistance development in the tumor cells is a major hur
treatment. Chemoresistance might be due to various factors, such as dle, and radio-resistance and tumor relapse are due to the activations of
changes in the tumor microenvironment, apoptotic pathway, and TFs like NF-κB [204]. Earlier studies showed that radio-resistance de
increased efflux of drug with impaired intake of drug [190,191]. Various velops irrespective of dose (whether taken in low or heavy concentra
drugs induce NF-κB activation and/or resistance in BC tumor cells. For tions) [205–210]. In addition, it has been reported that the clinical doses
instance, ABC (ATP binding cassette) proteins are widely expressed in trigger inter- and intra-cellular signaling, activating NF-κB and the
cancer cells, and MRP1 and MDR1, which are the members of this secretion of TNF-α via an NF-κB dependent pathway, and promote
transporters superfamily, are mostly accountable for the emergence of long-term positive input of NF-κB and TNF-α interaction [211]. Oct4
chemoresistance [192,193]. It was determined that NF-κB maintains (POU-domain octamer binding transcription factor 4) is commonly
cross talk with drug efflux proteins and is associated with their expres expressed in malignant tumor cells like those of BC and breast CSC. In
sion. This results in the upregulations of NF-κB, p65, Bcl-2, and the addition, Oct4 can promote chemoresistance by upregulating ABC pro
downregulation of Bax in doxorubicin-treated BC cells [194]. However, teins and radio-resistance is also associated with Oct4 expression. The
inhibiting the expression of NF-κB, p65 or its siRNA silencing could overexpression of Oct4 suppressed IR-induced premature senescence
block the translocation as well as reduce the expressions of MDR1 and subjected to ionizing radiation via IL-24 production activated by STAT3
MRP1. Wang et al. [195] determined that BC cells developed resistance and NF-κB that leads to resistance [212]. Furthermore, treatment with
against epirubicin due to the Akt/NF-κB induced over expression of the selenium compound ebselen and γ-radiation significantly improved
GPR120, which mediates the ABC transporter proteins over expression antitumor activity in MCF-7 tumor cell lines [89]. The selenium com
and the accumulation of epirubicin. However, sensitizing GPR120 with pounds force tumor cells against the redox threshold and eventually
an antagonist like AH7614 or GPR120 siRNA was found to decrease the promote apoptosis and sensitize cells to radiation [213–215]. Thus,
expressions of ABC proteins and enhance the epirubicin efficacy in strategies that target these pathways might be helpful for novel thera
MCF-7 cell lines. Thus, the authors suggested that GPR120 possibly a peutic interventions that minimize tumor recurrence.
potential therapeutic target to overcome the chemoresistance. As
documented earlier, RIP2 overexpression is allied with an inadequate
prognosis and cancer recurrence in TNBC. It was recently demonstrated
Table 1
Clinical Trials and study phases conducted on drugs and nanomedicines (Source: https://Clinicaltrials.gov).
Intervention/Drug/ Other Name Title Identifier Purpose Study/ Recruitment
Phase Status
Curcumin/ Treatment with Meriva in induced NCT01740323 To find out if the curcumin reduces binding of Phase II Completed
Meriva inflammation and fatigue with BC NF-κB to DNA and eventually with its
women downstream IL-6 in patients after
chemotherapy.
Ritonavir A Phase I/II trial of short course pre- NCT01009437 The phase I/II trial includes the best dose of Phase I Completed
operative Ritonavir to determine ritonavir and its effects in women undergoing
inhibition of Akt in BC. surgery for newly diagnosed BC
Gemcitabine/ Dietary supplement: Phase II trial of Gemcitabine and NCT00244933 The phase II trial includes the working of Phase II Completed
Genistein Genistein in metastatic BC patient. gemcitabine hydrochloride with genistein
in treating the women having stage IV BC
Imx-110 A phase I/IIa open-label, Dose NCT03382340 To determine safety and pharmacokinetic in Phase I Recruiting
(A nanoparticle encapsulated with -Escalation safety, tolerability and the patient with the advanced stage Phase II
STAT3/ NF-κB / poly-tyrosine kinase pharmacokinetic with advanced stage
inhibitor and doxorubicin in lower
dose)
9
5.3. NF-κB inhibitors in BC therapy Acknowledgement
Earlier, in vitro studies have provided proof-of-concept that the in This work was financed by National Research Foundation of Korea
hibition of NF-κB activation can reduce many pro-inflammatory effects. (NRF) grant sponsored by the Korea government (MSIT) (Grant no.
As a result of this, NF-κB is a compelling target for therapeutic inter 2021R1I1A1A01061115, 2021R1A2C3011585, and 2022R1A6A1A03
vention in BC. Although some medications are known to have some 051705).
indirect NF-κB blocking properties, very few direct inhibitors of NF-κB
are in use. These NF-κB inhibitors can reduce the activity of NF-κB and References
improves the BC treatment outcomes [216]. So far, Bortezomib, IKK
inhibitors, thalidomide and its analogs, and PARP inhibitors are being [1] H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal,
F. Bray, Global cancer statistics 2020: GLOBOCAN estimates of incidence and
investigated for BC therapy. Recently, Ji-Yeon et al. [217] found that mortality worldwide for 36 cancers in 185 countries, CA: A Cancer J. Clin. 71 (3)
Bortezomib inhibits Sp1 activity and interferes with the physical inter (2021) 209–249.
action of Sp1/p65, which results in downregulation of the NF-κB [2] I. Ahmad, Tamoxifen a pioneering drug: an update on the therapeutic potential of
tamoxifen derivatives, Eur. J. Med. Chem. 143 (2018) 515–531.
pathway. Although bortezomib showed anti-angiogenic properties in [3] R. Jahangiri, F. Mosaffa, A. Emami Razavi, L. Teimoori-Toolabi,
preclinical models of breast and other cancers, a phase I/II trial of K. Jamialahmadi, Altered DNA methyltransferases promoter methylation and
bortezomib and capecitabine combination therapy in patients with mRNA expression are associated with tamoxifen response in breast tumors,
J. Cell. Physiol. 233 (9) (2018) 7305–7319.
metastatic BC revealed only moderate antitumor activity [218]. Besides, [4] M.-G. Lee, S.G. Lee, K.-S. Nam, Ginkgolide B suppresses TPA-induced metastatic
IKK related kinases are important NF-κB regulators and their inhibitor potential in MCF-7 human breast cancer cells by inhibiting MAPK/AP-1 signaling,
IKK16 was more effective than gefitinib (an EGFR inhibitor) in reducing Biotechnol. Bioprocess Eng. 27 (6) (2022) 995–1003.
[5] N. Shah, A.S. Mohammad, P. Saralkar, S.A. Sprowls, S.D. Vickers, D. John, R.
the viability of TNBC cell lines. Therefore, the combination of IKK16
M. Tallman, B.P. Lucke-Wold, K.E. Jarrell, M. Pinti, Investigational chemotherapy
with gefitinib resulted in a synergistic antiproliferative effect [219]. In and novel pharmacokinetic mechanisms for the treatment of breast cancer brain
the mouse model, thalidomide is known to inhibit tumor growth by metastases, Pharmacol. Res. 132 (2018) 47–68.
inhibiting angiogenesis and necrosis of BC tumour cells [220]. [6] M. Arnold, E. Morgan, H. Rumgay, A. Mafra, D. Singh, M. Laversanne, J. Vignat,
J.R. Gralow, F. Cardoso, S. Siesling, I. Soerjomataram, Current and future burden
Furthermore, NF-κB inhibitors can be used alone or in combination with of breast cancer: global statistics for 2020 and 2040, Breast 66 (2022) 15–23.
other breast cancer therapies such as chemotherapy and radiation [7] D.D. Durham, L.A. Abraham, M.C. Roberts, C.P. Khan, R.A. Smith,
therapy. Extensive animal and human studies are needed to fully un K. Kerlikowske, D.L. Miglioretti, Breast cancer incidence among women with a
family history of breast cancer by relative’s age at diagnosis, Cancer 128 (24)
derstand the effectiveness and potential side effects of NF-κB inhibitors (2022) 4232–4240.
for breast cancer treatment. [8] M. Thun, M.S. Linet, J.R. Cerhan, C.A. Haiman, D. Schottenfeld, Cancer
Epidemiology and Prevention, Oxford University Press, 2017.
[9] N.S. Hegde, D.A. Sanders, R. Rodriguez, S. Balasubramanian, The transcription
6. Conclusions and future perspectives factor FOXM1 is a cellular target of the natural product thiostrepton, Nat. Chem.
3 (9) (2011) 725.
BC is a potentially fatal malignancy that results from genetic muta [10] A. Boija, I.A. Klein, B.R. Sabari, A. Dall’Agnese, E.L. Coffey, A.V. Zamudio, C.
H. Li, K. Shrinivas, J.C. Manteiga, N.M. Hannett, B.J. Abraham, L.K. Afeyan, Y.
tions and an unhealthy lifestyle. Dysregulated tumor suppressor genes E. Guo, J.K. Rimel, C.B. Fant, J. Schuijers, T.I. Lee, D.J. Taatjes, R.A. Young,
and oncogenes encode TFs that inhibit apoptosis, induce cell growth, Transcription factors activate genes through the phase-separation capacity of
cell cycle progression, and metastasis. NF-κB is a key regulator for their activation domains, Cell 175 (7) (2018) 1842–1855, e16.
[11] K. Vishnoi, N. Viswakarma, A. Rana, B. Rana, Transcription factors in cancer
various signalling pathways, including those responsible for resistance
development and therapy, Cancers 12 (8) (2020) 2296.
to chemotherapy and radiotherapies in various cancers, but especially in [12] M. Hui, A. Cazet, R. Nair, D.N. Watkins, S.A. O’Toole, A. Swarbrick, The
hormone-independent BC. Thus, targeting the aberrant molecular Hedgehog signalling pathway in breast development, carcinogenesis and cancer
signaling pathways of NF-κB might be a potential strategy for BC ther therapy, Breast Cancer Res 15 (2) (2013).
[13] S.D. Barth, J.J. Schulze, T. Kühn, E. Raschke, A. Hüsing, T. Johnson, R. Kaaks,
apy. Though conventional adjuvant therapies like chemo- and radio- S. Olek, Treg-mediated immune tolerance and the risk of solid cancers: findings
therapies are advantageous, but they have serious adverse side effects, from EPIC-heidelberg, JNCI: J. Natl. Cancer Ins. 107 (11) (2015).
which include resistance to chemotherapy and disease recurrence due to [14] F. Linke, M. Harenberg, M.M. Nietert, S. Zaunig, F. von Bonin, A. Arlt,
M. Szczepanowski, H.A. Weich, S. Lutz, C. Dullin, P. Janovská, M. Krafčíková,
the overactivation of NF-κB. Combination therapies aimed at inacti L. Trantírek, P. Ovesná, W. Klapper, T. Beissbarth, F. Alves, V. Bryja, L. Trümper,
vating NF-κB and sensitizing tumor cells have produced encouraging J. Wilting, D. Kube, Microenvironmental interactions between endothelial and
results, but these therapies should be locally and not systemically ad lymphoma cells: a role for the canonical WNT pathway in Hodgkin lymphoma,
Leukemia 31 (2) (2017) 361–372.
vantageous. Nanotechnology offers an attractive strategy for delivering [15] N. Wang, W. Liu, Y. Zheng, S. Wang, B. Yang, M. Li, J. Song, F. Zhang, X. Zhang,
drugs and conventional therapeutics to tumors and enhances drug Q. Wang, Z. Wang, CXCL1 derived from tumor-associated macrophages promotes
pharmacokinetics, efficacies, and retentions. Hence, developments that breast cancer metastasis via activating NF-κB/SOX4 signaling, Cell Death Dis. 9
(9) (2018).
target relevant molecular signaling pathways and TFs may result in [16] Z. Lin, L. Liao, S. Zhao, W. Gu, G. Wang, Z. Shen, Y. Wang, K. Chen, W. Liu, Y. Cai,
effective inhibitors of NF-κB that improve BC therapy. C. Wan, T. Yan, Corylin inhibits the progression of Non-small cell lung cancer
cells by regulating NF-κB signaling pathway via targeting p65, Phytomedicine
110 (2023), 154627.
CRediT authorship contribution statement
[17] X. Cheng, F. Wang, Y. Qiao, T. Chen, L. Fan, X. Shen, D. Yu, Y. Huang, M. Wei,
Honokiol inhibits interleukin-induced angiogenesis in the NSCLC
All authors contributed to the conceptualization of this review, E. microenvironment through the NF-κB signaling pathway, Chem. -Biol. Interact.
370 (2023), 110295.
Pavitra, J. Kancharla, VK Gupta, and BLVKS wrote the original draft. K.
[18] D. Que, F. Kuang, R. Kang, D. Tang, J. Liu, ACSS2-mediated NF-κB activation
Prasad, JG Kim, JY Sung, and M. B. Tej designed the figures and tables. promotes alkaliptosis in human pancreatic cancer cells, Sci. Rep. 13 (1) (2023)
R. Choi, J-H Lee, Y-K. Han, GSR Raju, LVKS Bhaskar, and YS Huh 1483.
reviewed and edited the manuscript. All the authors have read and [19] Z. Qian, L. Chen, J. Liu, Y. Jiang, Y. Zhang, The emerging role of PPAR-alpha in
breast cancer, Biomed. Pharmacother. 161 (2023), 114420.
agreed for the submission of the final version of the manuscript for [20] L. Koerner, M. Schmiel, T.-P. Yang, M. Peifer, R. Buettner, M. Pasparakis, NEMO-
publication. and RelA-dependent NF-κB signaling promotes small cell lung cancer, Cell Death
Differ. (2023).
[21] A. Chauhan, A.U. Islam, H. Prakash, S. Singh, Phytochemicals targeting NF-κB
Declaration of Competing Interest signaling: Potential anti-cancer interventions, J. Pharm. Anal. 12 (3) (2022)
394–405.
The authors declare that they have no known competing financial [22] N.D. Perkins, The diverse and complex roles of NF-κB subunits in cancer, Nat.
Rev. Cancer 12 (2) (2012) 121–132.
interests or personal relationships that could have appeared to influence
the work reported in this paper.
10
[23] R.R. Malla, P. Kiran, Tumor microenvironment pathways: Cross regulation in [50] M.J. Armstrong, M.T. Stang, Y. Liu, J. Yan, E. Pizzoferrato, J.H. Yim, IRF-1
breast cancer metastasis, Genes Dis. 9 (2) (2022) 310–324. inhibits NF-κB activity, suppresses TRAF2 and cIAP1 and induces breast cancer
[24] K. Yang, X. Wang, H. Zhang, Z. Wang, G. Nan, Y. Li, F. Zhang, M.K. Mohammed, cell specific growth inhibition, Cancer Biol. Ther. 16 (7) (2015) 1029–1041.
R.C. Haydon, H.H. Luu, Y. Bi, T.-C. He, The evolving roles of canonical WNT [51] G. Wu, L. Song, J. Zhu, Y. Hu, L. Cao, Z. Tan, S. Zhang, Z. Li, J. Li, An ATM/
signaling in stem cells and tumorigenesis: implications in targeted cancer TRIM37/NEMO axis counteracts genotoxicity by activating nuclear-to-
therapies, Lab. Invest. 96 (2) (2016) 116–136. cytoplasmic NF-κB signaling, Cancer Res 78 (22) (2018) 6399–6412.
[25] S.A. Piha-Paul, P.N. Munster, A. Hollebecque, G. Argilés, O. Dajani, J.D. Cheng, [52] C. Alberti, P. Pinciroli, B. Valeri, R. Ferri, A. Ditto, K. Umezawa, M. Sensi,
R. Wang, A. Swift, A. Tosolini, S. Gupta, Results of a phase 1 trial combining S. Canevari, A. Tomassetti, Ligand-dependent EGFR activation induces the co-
ridaforolimus and MK-0752 in patients with advanced solid tumours, Eur. J. expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial
Cancer 51 (14) (2015) 1865–1873. ovarian cancer, Oncogene 31 (37) (2012) 4139.
[26] T.D. Gilmore, The Re1/NF-kappa B/I kappa B signal transduction pathway and [53] J.G. Kim, K.C. Choi, C.W. Hong, H.S. Park, E.K. Choi, Y.S. Kim, J.B. Park, Tyr42
cancer, Cancer Treat. Res 115 (2003) 241–265. phosphorylation of RhoA GTPase promotes tumorigenesis through nuclear factor
[27] N. Yamaguchi, T. Ito, S. Azuma, E. Ito, R. Honma, Y. Yanagisawa, A. Nishikawa, (NF)-κB, Free Radic. Biol. Med 112 (2017) 69–83.
M. Kawamura, J.-I. Imai, S. Watanabe, K. Semba, J.-I. Inoue, Constitutive [54] Y. Tsuchiya, T. Asano, K. Nakayama, T. Kato, M. Karin, H. Kamata, Nuclear IKKβ
activation of nuclear factor-κB is preferentially involved in the proliferation of is an adaptor protein for IκBα ubiquitination and degradation in UV-Induced NF-
basal-like subtype breast cancer cell lines, Cancer Sci. 100 (9) (2009) 1668–1674. κB activation, Mol. Cell 39 (4) (2010) 570–582.
[28] M. Darweesh, S. Younis, Z. Hajikhezri, A. Ali, C. Jin, T. Punga, S. Gupta, [55] S. Liarte, J.L. Alonso-Romero, F.J. Nicolás, SIRT1 and estrogen signaling
M. Essand, L. Andersson, G. Akusjärvi, ZC3H11A loss of function enhances NF-κB cooperation for breast cancer onset and progression, Front. Endocrinol. 9 (2018).
signaling through defective IκBα protein expression, Front. Immunol. 13 (2022). [56] W. Yue, J.D. Yager, J.-P. Wang, E.R. Jupe, R.J. Santen, Estrogen receptor-
[29] F. Gómez-Chávez, D. Correa, P. Navarrete-Meneses, J.C. Cancino-Diaz, M. dependent and independent mechanisms of breast cancer carcinogenesis, Steroids
E. Cancino-Diaz, S. Rodríguez-Martínez, NF-κB and its regulators during 78 (2) (2013) 161–170.
pregnancy, Front. Immunol. 12 (2021). [57] J. Finlay-Schultz, B.M. Jacobsen, D. Riley, K.V. Paul, S. Turner, A. Ferreira-
[30] T. Liu, L. Zhang, D. Joo, S.-C. Sun, NF-κB signaling in inflammation, Signal Gonzalez, J.C. Harrell, P. Kabos, C.A. Sartorius, New generation breast cancer cell
Transduct. Target. Ther. 2 (1) (2017) 17023. lines developed from patient-derived xenografts, Breast Cancer Res 22 (1) (2020)
[31] W. Wang, S.A. Nag, R. Zhang, Targeting the NFκB signaling pathways for breast 68.
cancer prevention and therapy, Curr. Med. Chem. 22 (2) (2015) 264–289. [58] S. Van Laere, I. Van dA, G. Van den Eynden, H. Elst, J. Weyler, A. Harris, D.P. van,
[32] M. Devanaboyina, J. Kaur, E. Whiteley, L. Lin, K. Einloth, S. Morand, L. Stanbery, E.A. Van Marck, P.B. Vermeulen, L.Y. Dirix, Nuclear factor-kappaB signature of
D. Hamouda, J. Nemunaitis, NF-κB signaling in tumor pathways focusing on inflammatory breast cancer by cDNA microarray validated by quantitative real-
breast and ovarian cancer, Oncol. Rev. 16 (2022). time reverse transcription-PCR, immunohistochemistry, and nuclear factor-
[33] M. Liu, T. Sakamaki, M.C. Casimiro, N.E. Willmarth, A.A. Quong, X. Ju, J. Ojeifo, kappaB DNA-binding, Clin. Cancer Res 12 (2006) 3249–3256.
X. Jiao, W.S. Yeow, S. Katiyar, L.A. Shirley, D. Joyce, M.P. Lisanti, C. Albanese, R. [59] M. Cristofanilli, E.S. Singletary, G.N. Hortobagyi, Inflammatory breast carcinoma:
G. Pestell, The canonical NF-κB pathway governs mammary tumorigenesis in the sphinx of breast cancer research, J. Clin. Oncol. 22 (2) (2004) 381–383.
transgenic mice and tumor stem cell expansion, Cancer Res 70 (24) (2010) [60] X. Chen, T. Zhang, W. Su, Z. Dou, D. Zhao, X. Jin, H. Lei, J. Wang, X. Xie,
10464–10473. B. Cheng, Q. Li, H. Zhang, C. Di, Mutant p53 in cancer: from molecular
[34] R. Romieu-Mourez, D.W. Kim, S.M. Shin, E.G. Demicco, E. Landesman-Bollag, D. mechanism to therapeutic modulation, Cell Death Dis. 13 (11) (2022) 974.
C. Seldin, R.D. Cardiff, G.E. Sonenshein, Mouse mammary tumor virus c-rel [61] O.A. Sukocheva, E. Lukina, M. Friedemann, M. Menschikowski, A. Hagelgans,
transgenic mice develop mammary tumors, Mol. Cell. Bio. 23 (16) (2003) G. Aliev, The crucial role of epigenetic regulation in breast cancer anti-estrogen
5738–5754. resistance: current findings and future perspectives, Semin. Cancer Biol. 82
[35] A.F. Schott, M.D. Landis, G. Dontu, K.A. Griffith, R.M. Layman, I. Krop, L. (2022) 35–59.
A. Paskett, H. Wong, L.E. Dobrolecki, M.T. Lewis, A.M. Froehlich, J. Paranilam, D. [62] R. Divella, S. Tommasi, R. Lacalamita, A. Daniele, I. Abbate, V.M. Garrisi,
F. Hayes, M.S. Wicha, J.C. Chang, Preclinical and clinical studies of gamma E. Savino, M. Coviello, V. Rubini, G. Simone, Circulating hTERT DNA in early
secretase inhibitors with docetaxel on human breast tumors, Clin. Cancer Res 19 breast cancer, Anticancer Res 29 (7) (2009) 2845–2849.
(6) (2013) 1512–1524. [63] Y. Jin, B. Han, J. Chen, R. Wiedemeyer, S. Orsulic, S. Bose, X. Zhang, B.Y. Karlan,
[36] S.X. Atwood, R.J. Whitson, A.E. Oro, Advanced treatment for basal cell A.E. Giuliano, Y. Cui, FOXC1 is a critical mediator of EGFR function in human
carcinomas, Cold Spring Harb. Perspect. Med 4 (7) (2014). basal-like breast cancer, Ann. Surg. Oncol. 21 (4) (2014) 758–766.
[37] T. Zhang, C. Ma, Z. Zhang, H. Zhang, H. Hu, NF-κB signaling in inflammation and [64] S. Chung, Y. Jin, B. Han, Y. Qu, B. Gao, A.E. Giuliano, X. Cui, Identification of
cancer, MedComm 2 (4) (2021) 618–653. EGF-NF-κB-FOXC1 signaling axis in basal-like breast cancer, Cell Commun.
[38] K. Patil, S. Kuttikrishnan, A.Q. Khan, F. Ahmad, M. Alam, J. Buddenkotte, Signal. 15 (1) (2017) 22.
A. Ahmad, M. Steinhoff, S. Uddin, Molecular pathogenesis of Cutaneous T cell [65] L.L. Marotta, V. Almendro, A. Marusyk, M. Shipitsin, J. Schemme, S.R. Walker,
Lymphoma: role of chemokines, cytokines, and dysregulated signaling pathways, N. Bloushtain-Qimron, J.J. Kim, S.A. Choudhury, R. Maruyama, The JAK2/STAT3
Semin. Cancer Biol. 86 (2022) 382–399. signaling pathway is required for growth of CD44+ CD24–stem cell–like breast
[39] D. Morgan, M. Garg, V. Tergaonkar, S.Y. Tan, G. Sethi, Pharmacological cancer cells in human tumors, J. Clin. Invest 121 (7) (2011) 2723–2735.
significance of the non-canonical NF-κB pathway in tumorigenesis, iochim, [66] H. Lee, A. Herrmann, J.-H. Deng, M. Kujawski, G. Niu, Z. Li, S. Forman, R. Jove,
Biophys. Acta - Rev. Cancer 1874 (2) (2020), 188449. D.M. Pardoll, H. Yu, Persistently activated Stat3 maintains constitutive NF-κB
[40] S.C. Wei, L. Fattet, J.H. Tsai, Y. Guo, V.H. Pai, H.E. Majeski, A.C. Chen, R.L. Sah, activity in tumors, Cancer Cell 15 (4) (2009) 283–293.
S.S. Taylor, A.J. Engler, J. Yang, Matrix stiffness drives epithelial-mesenchymal [67] Z. Ji, L. He, A. Regev, K. Struhl, Inflammatory regulatory network mediated by
transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human
pathway, Nat. Cell Biol. 17 (5) (2015) 678–688. cancers, Proc. Natl. Acad. Sci. 116 (19) (2019) 9453–9462.
[41] B. Ruffell, A. Au, H.S. Rugo, L.J. Esserman, E.S. Hwang, L.M. Coussens, Leukocyte [68] J. Yu, Y. Wang, H. Li, X. Ren, Noncanonical NF-κB activation mediates STAT3-
composition of human breast cancer, Proc. Natl. Acad. Sci. U. S. A. 109 (8) (2012) stimulated IDO up-regulation in myeloid-derived suppressor cells in breast
2796–2801. cancer, AACR,, 2015.
[42] L. Al-mansoori, P. Elsinga, S.K. Goda, Bio-vehicles of cytotoxic drugs for delivery [69] Y. Wang, Z. Hu, J. Liang, Z. Wang, J. Tang, S. Wang, X. Wang, J. Qin, X. Wang,
to tumor specific targets for cancer precision therapy, Biomed. Pharmacother. H. Shen, A tandem repeat of human telomerase reverse transcriptase (hTERT) and
144 (2021), 112260. risk of breast cancer development and metastasis in Chinese women,
[43] D. Moher, D.J. Cook, S. Eastwood, I. Olkin, D. Rennie, D.F. Stroup, Improving the Carcinogenesis 29 (6) (2008) 1197–1201.
quality of reports of meta-analyses of randomised controlled trials: the QUOROM [70] S.S. Chung, C. Aroh, J.V. Vadgama, Constitutive activation of STAT3 signaling
statement, Lancet 354 (9193) (1999) 1896–1900. regulates hTERT and promotes stem cell-like traits in human breast cancer cells,
[44] M. Liu, T. Sakamaki, M.C. Casimiro, N.E. Willmarth, A.A. Quong, X. Ju, J. Ojeifo, PLoS One 8 (12) (2013), e83971.
X. Jiao, W.-S. Yeow, S. Katiyar, The canonical NF-κB pathway governs mammary [71] S.P. Egusquiaguirre, J.E. Yeh, S.R. Walker, S. Liu, D.A. Frank, The STAT3 target
tumorigenesis in transgenic mice and tumor stem cell expansion, Cancer Res 70 gene TNFRSF1A modulates the NF-κB pathway in breast Cancer cells, Neoplasia
(24) (2010) 10464–10473. 20 (5) (2018) 489–498.
[45] M. Du, C.K. Ea, Y. Fang, Z.J. Chen, Liquid phase separation of NEMO induced by [72] L.X. Li, J.X. Zhou, J.P. Calvet, A.K. Godwin, R.A. Jensen, X. Li, Lysine
polyubiquitin chains activates NF-κB, Mol. Cell 82 (13) (2022) 2415–2426, e5. methyltransferase SMYD2 promotes triple negative breast cancer progression,
[46] Y. Liu, K. Liu, Y. Huang, M. Sun, Q. Tian, S. Zhang, Y. Qin, TRIM25 Promotes Cell Death Dis. 9 (3) (2018) 326.
TNF-α–Induced NF-κB Activation through Potentiating the K63-Linked [73] H.S. Ban, M. Uno, H. Nakamura, Suppression of hypoxia-induced HIF-1α
Ubiquitination of TRAF2, J. Immunol. 204 (6) (2020) 1499–1507. accumulation by VEGFR inhibitors: Different profiles of AAL993 versus SU5416
[47] B. Razani, A.D. Reichardt, G. Cheng, Non-canonical NF-κB signaling activation and KRN633, Cancer Lett. 296 (1) (2010) 17–26.
and regulation: principles and perspectives, Immunol. Rev. 244 (1) (2011) 44–54. [74] C.-L. Chen, J.-S. Chu, W.-C. Su, S.-C. Huang, W.-Y. Lee, Hypoxia and metabolic
[48] F.J. Velloso, A.F. Bianco, J.O. Farias, N.E. Torres, P.Y. Ferruzo, V. Anschau, H. phenotypes during breast carcinogenesis: expression of HIF-1α, GLUT1, and
C. Jesus-Ferreira, T.H. Chang, M.C. Sogayar, L.F. Zerbini, R.G. Correa, The CAIX, Virchows Arch. 457 (1) (2010) 53–61.
crossroads of breast cancer progression: insights into the modulation of major [75] Q. Qiao, Y. Nozaki, K. Sakoe, N. Komatsu, K. Kirito, NF-κB mediates aberrant
signaling pathways, OncoTargets Ther. 10 (2017) 5491–5524. activation of HIF-1 in malignant lymphoma, Exp. Hematol. 38 (12) (2010)
[49] A.J. Baxendale, C.W. Dawson, S.E. Stewart, V. Mudaliar, G. Reynolds, J. Gordon, 1199–1208.
P.G. Murray, L.S. Young, A.G. Eliopoulos, Constitutive activation of the CD40 [76] L. Schito, G.L. Semenza, Hypoxia-inducible factors: master regulators of cancer
pathway promotes cell transformation and neoplastic growth, Oncogene 24 (53) progression, Trends Cancer 2 (12) (2016) 758–770.
(2005) 7913.
11
[77] S. Bonello, C. Za¨hringer, R.S. BelAiba, T. Djordjevic, J. Hess, C. Michiels, [104] H. Chua, P. Bhat-Nakshatri, S. Clare, A. Morimiya, S. Badve, H. Nakshatri, NF-κB
T. Kietzmann, A. Go¨rlach, Reactive oxygen species activate the HIF-1α promoter represses E-cadherin expression and enhances epithelial to mesenchymal
via a functional NFκB site, Arterioscler. Thromb. Vasc. Biol. 27 (4) (2007) transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2,
755–761. Oncogene 26 (5) (2007) 711.
[78] A. Tanimura, A. Nakazato, N. Tanaka, MYD88 signals induce tumour-initiating [105] M.A. Huber, N. Azoitei, B. Baumann, S. Grünert, A. Sommer, H. Pehamberger,
cell generation through the NF-κB-HIF-1α activation cascade, Sci. Rep. 11 (1) N. Kraut, H. Beug, T. Wirth, NF-κB is essential for epithelial-mesenchymal
(2021) 3991. transition and metastasis in a model of breast cancer progression, J. Clin. Invest
[79] D. Vordermark, Hypoxia-specific targets in cancer therapy: role of splice variants, 114 (4) (2004) 569–581.
BMC Med. 8 (1) (2010) 45. [106] H. Kim, W.J. Rhee, Exosome-mediated Let7c-5p delivery for breast cancer
[80] J.S. Zanetti, D.F. Soave, J.P. Oliveira-Costa, G.G. Da Silveira, L.N.Z. Ramalho, S. therapeutic development, Biotechnol. Bioprocess Eng. 25 (4) (2020) 513–520.
B. Garcia, S. Zucoloto, A. Ribeiro-Silva, The role of tumor hypoxia in MUC1- [107] M. Majumder, L. Dunn, L. Liu, A. Hasan, K. Vincent, M. Brackstone, D. Hess, P.
positive breast carcinomas, Virchows Arch. 459 (4) (2011) 367. K. Lala, COX-2 induces oncogenic micro RNA miR655 in human breast cancer,
[81] V. Sharma, D. Dixit, N. Koul, V.S. Mehta, E. Sen, Ras regulates interleukin-1β- Sci. Rep. 8 (1) (2018) 327.
induced HIF-1α transcriptional activity in glioblastoma, J. Mol. Med 89 (2) [108] A. Mao, M. Chen, Q. Qin, Z. Liang, W. Jiang, W. Yang, C. Wei, ZBTB7A promotes
(2011) 123–136. migration, invasion and metastasis of human breast cancer cells through NF-κB-
[82] J. Chen, X. Huang, N. Li, B. Liu, Z. Ma, J. Ling, W. Yang, T. Li, Narasin inhibits induced epithelial–mesenchymal transition in vitro and in vivo, J. Biochem 166
tumor metastasis and growth of ERα‑positive breast cancer cells by inactivation (6) (2019) 485–493.
of the TGF‑β/SMAD3 and IL‑6/STAT3 signaling pathways, Mol. Med Rep. 22 (6) [109] M. Al-Hajj, M.S. Wicha, A. Benito-Hernandez, S.J. Morrison, M.F. Clarke,
(2020) 5113–5124. Prospective identification of tumorigenic breast cancer cells, Proc. Natl. Acad. Sci.
[83] S. Liang, Z. Chen, G. Jiang, Y. Zhou, Q. Liu, Q. Su, W. Wei, J. Du, H. Wang, U. S. A. 100 (7) (2003) 3983–3988.
Activation of GPER suppresses migration and angiogenesis of triple negative [110] D. Ponti, A. Costa, N. Zaffaroni, G. Pratesi, G. Petrangolini, D. Coradini, S. Pilotti,
breast cancer via inhibition of NF-κB/IL-6 signals, Cancer Lett. 386 (2017) 12–23. M.A. Pierotti, M.G. Daidone, Isolation and in vitro propagation of tumorigenic
[84] A. Naldini, I. Filippi, D. Miglietta, M. Moschetta, R. Giavazzi, F. Carraro, breast cancer cells with stem/progenitor cell properties, Cancer Res 65 (13)
Interleukin-1β regulates the migratory potential of MDAMB231 breast cancer (2005) 5506–5511.
cells through the hypoxia-inducible factor-1α, Eur. J. Cancer 46 (18) (2010) [111] P.B. Gupta, T.T. Onder, G. Jiang, K. Tao, C. Kuperwasser, R.A. Weinberg, E.
3400–3408. S. Lander, Identification of selective inhibitors of cancer stem cells by high-
[85] I. Filippi, F. Carraro, A. Naldini, Interleukin-1β affects MDAMB231 breast cancer throughput screening, Cell 138 (4) (2009) 645–659.
cell migration under hypoxia: role of HIF-1α and NFκB transcription factors, [112] J.A. Joyce, J.W. Pollard, Microenvironmental regulation of metastasis, Nat. Rev.
Mediat. Inflamm. (2015)) (2015). Cancer 9 (4) (2009) 239.
[86] G. Carrà, L. Avalle, L. Seclì, M. Brancaccio, A. Morotti, Shedding Light on NF-κB [113] E.A. El-Ghonaimy, M. El-Shinawi, S.A. Ibrahim, H. El-Ghazaly, R. Abd-El-Tawab,
functions in cellular organelles, Front. Cell Dev. Biol. 10 (2022). M.A. Nouh, T. El-Mamlouk, M.M. Mohamed, Positive lymph-node breast cancer
[87] M.W. Lee, D.S. Kim, J.E. Eom, J.W. Lee, K.W. Sung, H.H. Koo, Y.B. Hong, K. patients–activation of NF-κB in tumor-associated leukocytes stimulates cytokine
H. Yoo, Dual role of ERK2/NF-κB signaling in TRAIL sensitivity, Am. J. Cancer secretion that promotes metastasis via C-C chemokine receptor CCR 7, FEBS J.
Res. 12 (7) (2022) 3373–3389. 282 (2) (2015) 271–282.
[88] S.M. Woo, K.-j Min, B.R. Seo, T.K. Kwon, YM155 sensitizes TRAIL-induced [114] M. Liu, X. Ju, N.E. Willmarth, M.C. Casimiro, J. Ojeifo, T. Sakamaki, S. Katiyar,
apoptosis through cathepsin S-dependent down-regulation of Mcl-1 and NF-κB- X. Jiao, V.M. Popov, Z. Yu, Nuclear factor-κB enhances ErbB2-induced mammary
mediated down-regulation of c-FLIP expression in human renal carcinoma Caki tumorigenesis and neoangiogenesis in vivo, Am. J. Pathol. 174 (5) (2009)
cells, Oncotarget 7 (38) (2016) 61520. 1910–1920.
[89] N.M. Thabet, E.M. Moustafa, Synergistic effect of ebselen and gamma radiation [115] N.B. Nataraj, B.P. Salimath, Crosstalk between VEGF and novel angiogenic
on breast cancer cells, Int. J. Radiat. Biol. 93 (8) (2017) 784–792. protein regulates tumor angiogenesis and contributes to aggressiveness of breast
[90] D. Del Bufalo, A. Biroccio, C. Leonetti, G. Zupi, Bcl-2 overexpression enhances the carcinoma, Cell. Signal. 25 (1) (2013) 277–294.
metastatic potential of a human breast cancer line, FASEB J. 11 (12) (1997) [116] J.W. Pollard, Macrophages define the invasive microenvironment in breast
947–953. cancer, J. Leukoc. Biol. 84 (3) (2008) 623–630.
[91] A. Kawiak, A. Kostecka, Regulation of Bcl-2 family proteins in estrogen receptor- [117] A. Mantovani, S. Sozzani, M. Locati, P. Allavena, A. Sica, Macrophage
positive breast cancer and their implications in endocrine therapy, Cancers polarization: tumor-associated macrophages as a paradigm for polarized M2
(Basel) 14 (2) (2022). mononuclear phagocytes, Trends Immunol. 23 (11) (2002) 549–555.
[92] R. Singh, A. Letai, K. Sarosiek, Regulation of apoptosis in health and disease: the [118] E.Y. Lin, J.-F. Li, L. Gnatovskiy, Y. Deng, L. Zhu, D.A. Grzesik, H. Qian, X.-N. Xue,
balancing act of BCL-2 family proteins, Nat. Rev. Mol. Cell Biol. 20 (3) (2019) J.W. Pollard, Macrophages regulate the angiogenic switch in a mouse model of
175–193. breast cancer, Cancer Res 66 (23) (2006) 11238–11246.
[93] L. Ren, Z. Li, C. Dai, D. Zhao, Y. Wang, C. Ma, C. Liu, Chrysophanol inhibits [119] M.A. Chaplain, S.R. McDougall, S. Anderson, Mathematical modelling of dynamic
proliferation and induces apoptosis through NF-κB/cyclin D1 and NF-κB/Bcl-2 adaptive tumour-induced angiogenesis: clinical implications and therapeutic
signaling cascade in breast cancer cell lines, Mol. Med. Rep. 17 (3) (2018) targeting strategies, J. Theor. Biol. 241 (3) (2006) 564–589.
4376–4382. [120] M. Weigand, P. Hantel, R. Kreienberg, J. Waltenberger, Autocrine vascular
[94] D.C. Guttridge, C. Albanese, J.Y. Reuther, R.G. Pestell, A.S. Baldwin, NF-κB endothelial growth factor signalling in breast cancer, Evid. Cell lines Prim. Breast
controls cell growth and differentiation through transcriptional regulation of Cancer Cult. Vitr., Angiogenesis 8 (3) (2005) 197–204.
cyclin D1, Mol. Cell. Biol. 19 (8) (1999) 5785–5799. [121] Y. Wang, X. Mo, M.G. Piper, H. Wang, N.L. Parinandi, D. Guttridge, C.B. Marsh,
[95] Y. Cao, G. Bonizzi, T.N. Seagroves, F.R. Greten, R. Johnson, E.V. Schmidt, M-CSF induces monocyte survival by activating NF-κB p65 phosphorylation at
M. Karin, IKKα provides an essential link between RANK signaling and cyclin D1 Ser276 via protein kinase C, PLoS One 6 (12) (2011), e28081.
expression during mammary gland development, Cell 107 (6) (2001) 763–775. [122] K. Horiuchi, T. Miyamoto, H. Takaishi, A. Hakozaki, N. Kosaki, Y. Miyauchi,
[96] Y.-C. Zhang, F.-C. Huo, L.-L. Wei, C.-C. Gong, Y.-J. Pan, J. Mou, D.-S. Pei, PAK5- M. Furukawa, J. Takito, H. Kaneko, K. Matsuzaki, Cell surface colony-stimulating
mediated phosphorylation and nuclear translocation of NF-κB-p65 promotes factor 1 can be cleaved by TNF-α converting enzyme or endocytosed in a clathrin-
breast cancer cell proliferation in vitro and in vivo, J. Exp. Clin. Cancer Res 36 (1) dependent manner, J. Immunol. 179 (10) (2007) 6715–6724.
(2017) 146. [123] D.C. Lee, S.W. Sunnarborg, C.L. Hinkle, T.J. Myers, M. Stevenson, W.E. Russell, B.
[97] X.-X. Wang, Q. Cheng, S.-N. Zhang, H.-Y. Qian, J.-X. Wu, H. Tian, D.-S. Pei, J.- J. Castner, M.J. Gerhart, R.J. Paxton, R.A. Black, TACE/ADAM17 processing of
N. Zheng, PAK5-Egr1-MMP2 signaling controls the migration and invasion in EGFR ligands indicates a role as a physiological convertase, Ann. N. Y. Acad. Sci.
breast cancer cell, Tumor Biol. 34 (5) (2013) 2721–2729. 995 (1) (2003) 22–38.
[98] Y.Y. Shen, Y. Yuan, Y.Y. Du, Y.Y. Pan, Molecular mechanism underlying the [124] R.A. Black, C.T. Rauch, C.J. Kozlosky, J.J. Peschon, J.L. Slack, M.F. Wolfson, B.
anticancer effect of simvastatin on MDA‑MB‑231 human breast cancer cells, Mol. J. Castner, K.L. Stocking, P. Reddy, S. Srinivasan, A metalloproteinase disintegrin
Med. Rep. 12 (1) (2015) 623–630. that releases tumour-necrosis factor-α from cells, Nature 385 (6618) (1997) 729.
[99] Q. Qin, Y. Xu, T. He, C. Qin, J. Xu, Normal and disease-related biological [125] P.A. Kenny, M.J. Bissell, Targeting TACE-dependent EGFR ligand shedding in
functions of Twist1 and underlying molecular mechanisms, Cell Res 22 (1) (2012) breast cancer, J. Clin. Invest 117 (2) (2007) 337–345.
90. [126] S.L. Rego, R.S. Helms, D. Dréau, Breast tumor cell TACE-shed MCSF promotes pro-
[100] C.-W. Li, W. Xia, L. Huo, S.-O. Lim, Y. Wu, J.L. Hsu, C.-H. Chao, H. Yamaguchi, N.- angiogenic macrophages through NF-κB signaling, Angiogenesis 17 (3) (2014)
K. Yang, Q. Ding, Epithelial–mesenchymal transition induced by TNF-α requires 573–585.
NF-κB–mediated transcriptional upregulation of Twist1, Cancer Res 72 (5) (2012) [127] R. Han, S. Gu, Y. Zhang, A. Luo, X. Jing, L. Zhao, X. Zhao, L. Zhang, Estrogen
1290–1300. promotes progression of hormone-dependent breast cancer through CCL2-CCR2
[101] S. Diep, M. Maddukuri, S. Yamauchi, G. Geshow, N.A. Delk, Interleukin-1 and axis by upregulation of Twist via PI3K/AKT/NF-κB signaling, Sci. Rep. 8 (1)
nuclear factor kappa B signaling promote breast cancer progression and treatment (2018) 9575.
resistance, Cells 11 (10) (2022) 1673. [128] M. Beleut, R.D. Rajaram, M. Caikovski, A. Ayyanan, D. Germano, Y. Choi,
[102] X. Wang, Y. Fang, W. Sun, Z. Xu, Y. Zhang, X. Wei, X. Ding, Y. Xu, P. Schneider, C. Brisken, Two distinct mechanisms underlie progesterone-induced
Endocrinotherapy resistance of prostate and breast cancer: Importance of the proliferation in the mammary gland, Proc. Natl. Acad. Sci. U. S. A. 107 (7) (2010)
NF‑κB pathway (Review), Int J. Oncol. 56 (5) (2020) 1064–1074. 2989–2994.
[103] J.T. Zhang, X.H. Jiang, C. Xie, H. Cheng, J. Da Dong, Y. Wang, K.L. Fok, X. [129] M.-L. Asselin-Labat, F. Vaillant, J.M. Sheridan, B. Pal, D. Wu, E.R. Simpson,
H. Zhang, T.T. Sun, L.L. Tsang, Downregulation of CFTR promotes epithelial-to- H. Yasuda, G.K. Smyth, T.J. Martin, G.J. Lindeman, Control of mammary stem cell
mesenchymal transition and is associated with poor prognosis of breast cancer, function by steroid hormone signalling, Nature 465 (7299) (2010) 798.
Biochim. Biophys. Acta, Mol. Cell Res. 1833 (12) (2013) 2961–2969.
12
[130] P.A. Joshi, H.W. Jackson, A.G. Beristain, M.A. Di Grappa, P.A. Mote, C.L. Clarke, [155] P.C. Cogswell, D.C. Guttridge, W.K. Funkhouser, A.S. Baldwin, Selective
J. Stingl, P.D. Waterhouse, R. Khokha, Progesterone induces adult mammary stem activation of NF-κB subunits in human breast cancer: potential roles for NF-κB2/
cell expansion, Nature 465 (7299) (2010) 803. p52 and for Bcl-3, Oncogene 19 (9) (2000) 1123.
[131] A. Mukherjee, S.M. Soyal, J. Li, Y. Ying, B. He, F.J. DeMayo, J.P. Lydon, Targeting [156] N.D. Mineva, X. Wang, S. Yang, H. Ying, Z.X.J. Xiao, M.F. Holick, G.
RANKL to a specific subset of murine mammary epithelial cells induces ordered E. Sonenshein, Inhibition of RelB by 1, 25–dihydroxyvitamin D3 promotes
branching morphogenesis and alveologenesis in the absence of progesterone sensitivity of breast cancer cells to radiation, J. Cell. Physiol. 220 (3) (2009)
receptor expression, FASEB J. 24 (11) (2010) 4408–4419. 593–599.
[132] H.G. Kim, J.Y. Kim, E.H. Han, Y.P. Hwang, J.H. Choi, B.H. Park, H.G. Jeong, [157] J.S. Boehm, J.J. Zhao, J. Yao, S.Y. Kim, R. Firestein, I.F. Dunn, S.K. Sjostrom, L.
Metallothionein-2A overexpression increases the expression of matrix A. Garraway, S. Weremowicz, A.L. Richardson, Integrative genomic approaches
metalloproteinase-9 and invasion of breast cancer cells, FEBS Lett. 585 (2) (2011) identify IKBKE as a breast cancer oncogene, Cell 129 (6) (2007) 1065–1079.
421–428. [158] R.R. Shen, A.Y. Zhou, E. Kim, E. Lim, H. Habelhah, W.C. Hahn, IκB kinase ε
[133] A.R. Farina, L. Cappabianca, G. DeSantis, N. Di Ianni, P. Ruggeri, M. Ragone, phosphorylates TRAF2 to promote mammary epithelial cell transformation, Mol.
S. Merolle, K.F. Tonissen, A. Gulino, A.R. Mackay, Thioredoxin stimulates MMP-9 Cell. Biol. 32 (23) (2012) 4756–4768.
expression, de-regulates the MMP-9/TIMP-1 equilibrium and promotes MMP-9 [159] H. Kiefel, S. Bondong, M. Pfeifer, U. Schirmer, N. Erbe-Hoffmann, H. Schäfer,
dependent invasion in human MDA-MB-231 breast cancer cells, FEBS Lett. 585 S. Sebens, P. Altevogt, EMT-associated up-regulation of L1CAM provides insights
(20) (2011) 3328–3336. into L1CAM-mediated integrin signalling and NF-κB activation, Carcinogenesis 33
[134] M.A. Rivas, M. Tkach, W. Beguelin, C.J. Proietti, C. Rosemblit, E.H. Charreau, P. (10) (2012) 1919–1929.
V. Elizalde, R. Schillaci, Transactivation of ErbB-2 induced by tumor necrosis [160] M.F. Kendellen, J.W. Bradford, C.L. Lawrence, K.S. Clark, A.S. Baldwin, Canonical
factor α promotes NF-κB activation and breast cancer cell proliferation, Breast and non-canonical NF-κB signaling promotes breast cancer tumor-initiating cells,
Cancer Res. Treat. 122 (1) (2010) 111–124. Oncogene 33 (10) (2014) 1297.
[135] Y.X. Lim, H. Lin, T. Chu, Y.P. Lim, WBP2 promotes BTRC mRNA stability to drive [161] W. Zhang, S.I. Grivennikov, Top Notch cancer stem cells by paracrine NF-κB
migration and invasion in triple-negative breast cancer via NF-κB activation, Mol. signaling in breast cancer, Breast Cancer Res 15 (5) (2013) 316.
Oncol. 16 (2) (2022) 422–446. [162] J. Bash, W.X. Zong, S. Banga, A. Rivera, D.W. Ballard, Y. Ron, C. Gélinas, Rel/NF-
[136] M. Zhang, Z.Z. Liu, K. Aoshima, W.L. Cai, H. Sun, T. Xu, Y. Zhang, Y. An, J. κB can trigger the Notch signaling pathway by inducing the expression of
F. Chen, L.H. Chan, A. Aoshima, S.M. Lang, Z. Tang, X. Che, Y. Li, S.J. Rutter, Jagged1, a ligand for Notch receptors, EMBO J. 18 (10) (1999) 2803–2811.
V. Bossuyt, X. Chen, J.S. Morrow, L. Pusztai, D.L. Rimm, M. Yin, Q. Yan, CECR2 [163] L. Li, F. Zhao, J. Lu, T. Li, H. Yang, C. Wu, Y. Liu, Notch-1 signaling promotes the
drives breast cancer metastasis by promoting NF-κB signaling and macrophage- malignant features of human breast cancer through NF-κB activation, PLoS One 9
mediated immune suppression, Sci. Transl. Med. 14 (630) (2022) eabf5473. (4) (2014), e95912.
[137] R.T. Sabra, A.A. Abdellatef, E. Abdel-Sattar, M. Fathy, M.R. Meselhy, [164] S. González-Reyes, J.M. Fernández, L.O. González, A. Aguirre, A. Suárez, J.
Y. Hayakawa, A. Russelioside, A pregnane glycoside from caralluma tuberculate, M. González, S. Escaff, F.J. Vizoso, Study of TLR3, TLR4, and TLR9 in prostate
inhibits cell-intrinsic NF-κB activity and metastatic ability of breast cancer cells, carcinomas and their association with biochemical recurrence, Cancer Immunol.
Biol. Pharm. Bull. 45 (10) (2022) 1564–1571. Immunother. 60 (2) (2011) 217–226.
[138] M. Jasin, Homologous repair of DNA damage and tumorigenesis: the BRCA [165] B. Fernandez-Garcia, N. Eiró, S. González-Reyes, L. González, A. Aguirre, L.
connection, Oncogene 21 (58) (2002) 8981. O. González, J.M. del Casar, J.L. García-Muñiz, F.J. Vizoso, Clinical significance
[139] K. Schlacher, H. Wu, M. Jasin, A distinct replication fork protection pathway of toll-like receptor 3, 4, and 9 in gastric cancer, J. Immunother. 37 (2) (2014)
connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2, Cancer Cell 22 77–83.
(1) (2012) 106–116. [166] D. Jia, W. Yang, L. Li, H. Liu, Y. Tan, S. Ooi, L. Chi, L.G. Filion, D. Figeys, L. Wang,
[140] T.T. Paull, Mechanisms of ATM activation, Annu. Rev. Biochem. 84 (2015) β-Catenin and NF-κB co-activation triggered by TLR3 stimulation facilitates stem
711–738. cell-like phenotypes in breast cancer, Cell Death Differ. 22 (2) (2015) 298.
[141] Z.-H. Wu, Y. Shi, R.S. Tibbetts, S. Miyamoto, Molecular linkage between the [167] J.V. McCarthy, J. Ni, V.M. Dixit, RIP2 is a novel NF-κB-activating and cell death-
kinase ATM and NF-κB signaling in response to genotoxic stimuli, Science 311 inducing kinase, J. Biol. Chem. 273 (27) (1998) 16968–16975.
(5764) (2006) 1141–1146. [168] M. Thome, K. Hofmann, K. Burns, F. Martinon, J.-L. Bodmer, C. Mattmann,
[142] Z.H. Wu, S. Miyamoto, Induction of a pro-apoptotic ATM–NF-κB pathway and its J. Tschopp, Identification of CARDIAK, a RIP-like kinase that associates with
repression by ATR in response to replication stress, EMBO J. 27 (14) (2008) caspase-1, Curr. Biol. 8 (15) (1998) 885–889.
1963–1973. [169] C. Lupfer, P.G. Thomas, P.K. Anand, P. Vogel, S. Milasta, J. Martinez, G. Huang,
[143] M. Volcic, S. Karl, B. Baumann, D. Salles, P. Daniel, S. Fulda, L. Wiesmüller, NF-κB M. Green, M. Kundu, H. Chi, Receptor interacting protein kinase 2–mediated
regulates DNA double-strand break repair in conjunction with BRCA1–CtIP mitophagy regulates inflammasome activation during virus infection, Nat.
complexes, Nucleic Acids Res 40 (1) (2011) 181–195. Immunol. 14 (5) (2013) 480.
[144] B. Gu, W.-G. Zhu, Surf the post-translational modification network of p53 [170] J.G. Magalhaes, J. Lee, K. Geddes, S. Rubino, D.J. Philpott, S.E. Girardin, Essential
regulation, Int. J. Biol. Sci. 8 (5) (2012) 672. role of Rip2 in the modulation of innate and adaptive immunity triggered by
[145] F. Kruiswijk, C.F. Labuschagne, K.H. Vousden, p53 in survival, death and Nod1 and Nod2 ligands, Eur. J. Immunol. 41 (5) (2011) 1445–1455.
metabolic health: a lifeguard with a licence to kill, Nat. Rev. Mol. Cell Biol. 16 (7) [171] J.T. Tigno-Aranjuez, J.M. Asara, D.W. Abbott, Inhibition of RIP2’s tyrosine kinase
(2015) 393. activity limits NOD2-driven cytokine responses, Genes Dev. 24 (23) (2010)
[146] A.S. Cerquido, M. Vojtek, R. Ribeiro-Oliveira, S. Gonçalves-Monteiro, M. 2666–2677.
J. Barroca, A. Moreira da Silva, O. Viegas, V. Freitas, J.B. Sousa, I.M.P.L.V. [172] S.M. Singel, K. Batten, C. Cornelius, G. Jia, G. Fasciani, S.L. Barron, W.E. Wright,
O. Ferreira, C. Diniz, Corema album leaves mediate DNA damage in triple- J.W. Shay, Receptor-interacting protein kinase 2 promotes triple-negative breast
negative breast cancer cells, Curr. Issues Mol. Biol. 44 (8) (2022) 3598–3610. cancer cell migration and invasion via activation of nuclear factor-kappaB and c-
[147] G. Schneider, A. Henrich, G. Greiner, V. Wolf, A. Lovas, M. Wieczorek, T. Wagner, Jun N-terminal kinase pathways, Breast Cancer Res 16 (2) (2014) R28.
S. Reichardt, A. Von Werder, R. Schmid, Cross talk between stimulated NF-κB and [173] D. Sarkar, D. Jana, P. Patil, K. Chaudhari, B. Chattopadhyay, B. Chikkala,
the tumor suppressor p53, Oncogene 29 (19) (2010) 2795. S. Mandal, P. Chowdhary, Role of NF-κB as a prognostic marker in breast cancer: a
[148] T. Cooks, I.S. Pateras, O. Tarcic, H. Solomon, A.J. Schetter, S. Wilder, G. Lozano, pilot study in Indian patients, Indian J. Surg. Oncol. 4 (3) (2013) 242–247.
E. Pikarsky, T. Forshew, N. Rozenfeld, Mutant p53 prolongs NF-κB activation and [174] N. Yamaguchi, T. Ito, S. Azuma, E. Ito, R. Honma, Y. Yanagisawa, A. Nishikawa,
promotes chronic inflammation and inflammation-associated colorectal cancer, M. Kawamura, Ji Imai, S. Watanabe, Constitutive activation of nuclear factor-κB
Cancer Cell 23 (5) (2013) 634–646. is preferentially involved in the proliferation of basal-like subtype breast cancer
[149] A.K. Frank, I. Julia, J. Leu, Y. Zhou, K. Devarajan, T. Nedelko, A. Klein-Szanto, cell lines, Cancer Sci. 100 (9) (2009) 1668–1674.
M. Hollstein, M.E. Murphy, The codon 72 polymorphism of p53 regulates [175] D. Börnigen, S. Tyekucheva, X. Wang, J.R. Rider, G.-S. Lee, L.A. Mucci,
interaction with NF-κB and transactivation of genes involved in immunity and C. Sweeney, C. Huttenhower, Computational reconstruction of NFκB pathway
inflammation, Mol. Cell. Biol. 31 (6) (2011) 1201–1213. interaction mechanisms during prostate cancer, PLoS Comput. Biol. 12 (4)
[150] T. Wagner, N. Kiweler, K. Wolff, S.K. Knauer, A. Brandl, P. Hemmerich, J.- (2016), e1004820.
H. Dannenberg, T. Heinzel, G. Schneider, O.H. Krämer, Sumoylation of HDAC2 [176] F. Li, G. Sethi, Targeting transcription factor NF-κB to overcome chemoresistance
promotes NF-κB-dependent gene expression, Oncotarget 6 (9) (2015) 7123. and radioresistance in cancer therapy, Biochim. Biophys. Acta, Rev. Cancer 1805
[151] C. Schäfer, A. Göder, M. Beyer, N. Kiweler, N. Mahendrarajah, A. Rauch, (2) (2010) 167–180.
T. Nikolova, N. Stojanovic, M. Wieczorek, T.R. Reich, Class I histone deacetylases [177] L. Sas, F. Lardon, P.B. Vermeulen, J. Hauspy, P. Van Dam, P. Pauwels, L.Y. Dirix,
regulate p53/NF-κB crosstalk in cancer cells, Cell. Signal. 29 (2017) 218–225. S.J. Van Laere, The interaction between ER and NFκB in resistance to endocrine
[152] L. Weisz, A. Damalas, M. Liontos, P. Karakaidos, G. Fontemaggi, R. Maor-Aloni, therapy, Breast Cancer Res 14 (4) (2012) 212.
M. Kalis, M. Levrero, S. Strano, V.G. Gorgoulis, Mutant p53 enhances nuclear [178] S. Van Laere, I. Van der Auwera, G. Van den Eynden, P. Van Dam, E. Van Marck,
factor κB activation by tumor necrosis factor α in cancer cells, Cancer Res 67 (6) P. Vermeulen, L. Dirix, NF-κB activation in inflammatory breast cancer is
(2007) 2396–2401. associated with oestrogen receptor downregulation, secondary to EGFR and/or
[153] H. Jin, X. Wang, J. Ying, A.H.Y. Wong, H. Li, K.Y. Lee, G. Srivastava, A.T. Chan, ErbB2 overexpression and MAPK hyperactivation, Br. J. Cancer 97 (5) (2007)
W. Yeo, B.B. Ma, Epigenetic identification of ADAMTS18 as a novel 16q23. 1 659.
tumor suppressor frequently silenced in esophageal, nasopharyngeal and multiple [179] J.S. Parker, M. Mullins, M.C. Cheang, S. Leung, D. Voduc, T. Vickery, S. Davies,
other carcinomas, Oncogene 26 (53) (2007) 7490. C. Fauron, X. He, Z. Hu, Supervised risk predictor of breast cancer based on
[154] Z. Xue, Z. Yi, X. Li, Y. Li, M. Jiang, H. Liu, S. Zeng, Upconversion optical/magnetic intrinsic subtypes, J. Clin. Oncol. 27 (8) (2009) 1160.
resonance imaging-guided small tumor detection and in vivo tri-modal [180] H. Nakshatri, P. Bhat-Nakshatri, D.A. Martin, R.J. Goulet, G.W. Sledge,
bioimaging based on high-performance luminescent nanorods, Biomaterials 115 Constitutive activation of NF-kappaB during progression of breast cancer to
(2017) 90–103. hormone-independent growth, Mol. Cell. Biol. 17 (7) (1997) 3629–3639.
13
[181] M.A. Sovak, R.E. Bellas, D.W. Kim, G.J. Zanieski, A.E. Rogers, A.M. Traish, G. tumorigenic breast cancer cells to chemotherapy, J. Natl. Cancer Inst. 100 (9)
E. Sonenshein, Aberrant nuclear factor-kappaB/Rel expression and the (2008) 672–679.
pathogenesis of breast cancer, J. Clin. Invest 100 (12) (1997) 2952–2960. [201] S. Saha, S. Mukherjee, M. Mazumdar, A. Manna, P. Khan, A. Adhikary, K. Kajal,
[182] Y. Cao, M. Karin, NF-κB in mammary gland development and breast cancer, D. Jana, G. Sa, S. Mukherjee, Mithramycin A sensitizes therapy-resistant breast
J. Mammary Gland Biol. Neoplasia 8 (2) (2003) 215–223. cancer stem cells toward genotoxic drug doxorubicin, Transl. Res. 165 (5) (2015)
[183] Y. Zhou, S. Eppenberger-Castori, C. Marx, C. Yau, G.K. Scott, U. Eppenberger, C. 558–577.
C. Benz, Activation of nuclear factor-κB (NFκB) identifies a high-risk subset of [202] A. Papi, T. Guarnieri, G. Storci, D. Santini, C. Ceccarelli, M. Taffurelli, S. De
hormone-dependent breast cancers, Int. J. Biochem. Cell Biol. 37 (5) (2005) Carolis, N. Avenia, A. Sanguinetti, A. Sidoni, Nuclear receptors agonists exert
1130–1144. opposing effects on the inflammation dependent survival of breast cancer stem
[184] L. DeGraffenried, B. Chandrasekar, W. Friedrichs, E. Donzis, J. Silva, M. Hidalgo, cells, Cell Death Differ. 19 (7) (2012) 1208.
J.W. Freeman, G. Weiss, NF-κB inhibition markedly enhances sensitivity of [203] S. Saha, S. Mukherjee, P. Khan, K. Kajal, M. Mazumdar, A. Manna, S. Mukherjee,
resistant breast cancer tumor cells to tamoxifen, Ann. Oncol. 15 (6) (2004) S. De, D. Jana, D.K. Sarkar, Aspirin suppresses the acquisition of chemoresistance
885–890. in breast cancer by disrupting an NFκB–IL6 signaling axis responsible for the
[185] M. Pradhan, L.A. Bembinster, S.C. Baumgarten, J. Frasor, Proinflammatory generation of cancer stem cells, Cancer Res 76 (7) (2016) 2000–2012.
cytokines enhance estrogen-dependent expression of the multidrug transporter [204] C. Galeaz, C. Totis, A. Bisio, Radiation resistance: a matter of transcription factors,
gene ABCG2 through estrogen receptor and NFκB cooperativity at adjacent Front. Oncol. 11 (2021), 662840.
response elements, J. Biol. Chem. 285 (41) (2010) 31100–31106. [205] N. Mohan, M.L. Meltz, Induction of nuclear factor κB after low-dose ionizing
[186] S. Djebali, C.A. Davis, A. Merkel, A. Dobin, T. Lassmann, A. Mortazavi, A. Tanzer, radiation involves a reactive oxygen intermediate signaling pathway, Radiat. Res.
J. Lagarde, W. Lin, F. Schlesinger, Landscape of transcription in human cells, 140 (1) (1994) 97–104.
Nature 489 (7414) (2012) 101. [206] M. Natarajan, R.J. Reiter, M.L. Meltz, T.S. Herman, Effect of melatonin on cell
[187] N.J. Vickers, Animal communication: when i’m calling you, will you answer too? growth, metabolic activity, and cell cycle distribution, J. Pineal Res. 31 (3) (2001)
Curr. Biol. 27 (14) (2017) R713–R715. 228–233.
[188] Z. Wang, D. Katsaros, N. Biglia, Y. Shen, L. Loo, X. Yu, H. Lin, Y. Fu, W.-M. Chu, [207] A.V. Prasad, N. Mohan, B. Chandrasekar, M.L. Meltz, Induction of transcription
P. Fei, ERα upregulates the expression of long non-coding RNA LINC00472 which of" immediate early genes" by low-dose ionizing radiation, Radiat. Res. 143 (3)
suppresses the phosphorylation of NF-κB in breast cancer, Breast Cancer Res. (1995) 263–272.
Treat. 175 (2) (2019) 353–368. [208] F. Pajonk, C.-S. Chiang, J.-R. Sun, W.H. McBride, NF-κB, cytokines, proteasomes,
[189] I. Kastrati, M.I. Siklos, S.D. Brovkovych, G.R.J. Thatcher, J. Frasor, A. Novel, and low-dose radiation exposure, Mil. Med. 167 (suppl_1) (2002) 66–67.
Strategy to co-target estrogen receptor and nuclear factor κB pathways with [209] T. Wang, Y.-C. Hu, S. Dong, M. Fan, D. Tamae, M. Ozeki, Q. Gao, D. Gius, J.J. Li,
hybrid drugs for breast cancer therapy, Horm Cancer 8 (3) (2017) 135–142. Co-activation of ERK, NF-κB, and GADD45β in response to ionizing radiation,
[190] S. Taylor, E.P. Spugnini, Y.G. Assaraf, T. Azzarito, C. Rauch, S. Fais, J. Biol. Chem. 280 (13) (2005) 12593–12601.
Microenvironment acidity as a major determinant of tumor chemoresistance: [210] M.A. Coleman, S.P. Sasi, J. Onufrak, M. Natarajan, K. Manickam, J. Schwab,
proton pump inhibitors (PPIs) as a novel therapeutic approach, Drug Resist. S. Muralidharan, L.E. Peterson, Y.O. Alekseyev, X. Yan, Low-dose radiation affects
Updates 23 (2015) 69–78. cardiac physiology: gene networks and molecular signaling in cardiomyocytes,
[191] S. Thomas, B.A. Quinn, S.K. Das, R. Dash, L. Emdad, S. Dasgupta, X.-Y. Wang, Am. J. Physiol. - Heart Circ. Physiol. 309 (11) (2015) H1947–H1963.
P. Dent, J.C. Reed, M. Pellecchia, Targeting the Bcl-2 family for cancer therapy, [211] H. Yu, N. Aravindan, J. Xu, M. Natarajan, Inter-and intra-cellular mechanism of
Expert Opin. Ther. Targets 17 (1) (2013) 61–75. NF-kB-dependent survival advantage and clonal expansion of radio-resistant
[192] K. Noguchi, K. Katayama, Y. Sugimoto, Human ABC transporter ABCG2/BCRP cancer cells, Cell. Signal. 31 (2017) 105–111.
expression in chemoresistance: basic and clinical perspectives for molecular [212] J.-Y. Kim, J.-C. Kim, J.-Y. Lee, M.-J. Park, Oct4 suppresses IR‑induced premature
cancer therapeutics, Pharm. Pers. Med. 7 (2014) 53. senescence in breast cancer cells through STAT3-and NF‑κB-mediated IL‑24
[193] D.E. Baxter, B. Kim, A.M. Hanby, E.T. Verghese, A.H. Sims, T.A. Hughes, production, Int. J. Oncol. 53 (1) (2018) 47–58.
Neoadjuvant endocrine therapy in breast cancer upregulates the cytotoxic drug [213] S.J. Kim, M.C. Choi, J.M. Park, A.S. Chung, Antitumor effects of selenium, Int J.
pump ABCG2/BCRP, and may lead to resistance to subsequent chemotherapy, Mol. Sci. 22 (21) (2021).
Clin. Breast Cancer 18 (6) (2018) 481–488. [214] Y. Chang, L. He, Z. Li, L. Zeng, Z. Song, P. Li, L. Chan, Y. You, X.-F. Yu, P.K. Chu,
[194] K. Velaei, N. Samadi, S. Soltani, B. Barazvan, J.S. Rad, NFκBP65 transcription T. Chen, Designing core–shell gold and selenium nanocomposites for cancer
factor modulates resistance to doxorubicin through ABC transporters in breast radiochemotherapy, ACS Nano 11 (5) (2017) 4848–4858.
cancer, Breast Cancer 24 (4) (2017) 552–561. [215] W. Liu, X. Li, Y.-S. Wong, W. Zheng, Y. Zhang, W. Cao, T. Chen, Selenium
[195] X. Wang, S. He, Y. Gu, Q. Wang, X. Chu, M. Jin, L. Xu, Q. Wu, Q. Zhou, B. Wang, nanoparticles as a carrier of 5-fluorouracil to achieve anticancer synergism, ACS
Fatty acid receptor GPR120 promotes breast cancer chemoresistance by Nano 6 (8) (2012) 6578–6591.
upregulating ABC transporters expression and fatty acid synthesis, EBioMedicine [216] S.M. Abdin, M.F. Tolba, D.M. Zaher, H.A. Omar, Nuclear factor-κB signaling
40 (2019) 251–262. inhibitors revert multidrug-resistance in breast cancer cells, Chem. Biol. Interact.
[196] R. Jaafar, K. Mnich, S. Dolan, J. Hillis, A. Almanza, S.E. Logue, A. Samali, A. 340 (2021), 109450.
M. Gorman, RIP2 enhances cell survival by activation of NF-ĸB in triple negative [217] J.-Y. Kim, H.H. Jung, S. Ahn, S. Bae, S.K. Lee, S.W. Kim, J.E. Lee, S.J. Nam, J.
breast cancer cells, Biochem. Biophys. Res. Commun. 497 (1) (2018) 115–121. S. Ahn, Y.-H. Im, Y.H. Park, The relationship between nuclear factor (NF)-κB
[197] H. Korkaya, G. Kim, A. Davis, F. Malik, N. Henry, S. Ithimakin, A. Quraishi, family gene expression and prognosis in triple-negative breast cancer (TNBC)
N. Tawakkol, R. D, Angelo, A.K. Paulson, S. Chung, T. Luther, H.J. Paholak, S. Liu, patients receiving adjuvant doxorubicin treatment, Sci. Rep. 6 (1) (2016) 31804.
K.A. Hassan, Q. Zen, S.G. Clouthier, M.S. Wicha, Activation of an IL6 [218] P. Schmid, D. Kühnhardt, P. Kiewe, S. Lehenbauer-Dehm, W. Schippinger,
inflammatory loop mediates trastuzumab resistance in HER2þ breast cancer by R. Greil, W. Lange, J. Preiss, N. Niederle, P. Brossart, W. Freier, S. Kümmel,
expanding the cancer stem cell population, Mol. Cell 47 (2012) 570–584. H. Van de Velde, A. Regierer, K. Possinger, A phase I/II study of bortezomib and
[198] W.C. Ho, K.M. Dickson, P.A. Barker, Nuclear factor-κB induced by doxorubicin is capecitabine in patients with metastatic breast cancer previously treated with
deficient in phosphorylation and acetylation and represses nuclear factor- taxanes and/or anthracyclines, Ann. Oncol. 19 (5) (2008) 871–876.
κB–dependent transcription in cancer cells, Cancer Res 65 (10) (2005) [219] Y.W. Yi, K.S. You, S. Han, I.J. Ha, J.-S. Park, S.-G. Lee, Y.-S. Seong, Inhibition of
4273–4281. IκB kinase is a potential therapeutic strategy to circumvent resistance to
[199] B. Yin, Z. Ma, Z. Zhou, W. Gao, Z. Du, Z. Zhao, Q. Li, The TrkB+ cancer stem cells epidermal growth factor receptor inhibition in triple-negative breast cancer cells,
contribute to post-chemotherapy recurrence of triple-negative breast cancers in Cancers 14 (21) (2022) 5215.
an orthotopic mouse model, Oncogene 34 (6) (2015) 761. [220] X. Wang, Y. Shen, L. MengLv, X. Zhang, J. Yang, F. Wang, J. Yang, Thalidomide
[200] X. Li, M.T. Lewis, J. Huang, C. Gutierrez, C.K. Osborne, M.-F. Wu, S. suppresses breast cancer tumor growth by inhibiting tumor-associated
G. Hilsenbeck, A. Pavlick, X. Zhang, G.C. Chamness, Intrinsic resistance of macrophage accumulation in breast tumor-bearing mice, Eur. J. Pharm. Sci. 151
(2020), 105302.
14

peran nfkb dan breast cancer

Uploaded by

Copyright:

Available Formats

peran nfkb dan breast cancer

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

peran nfkb dan breast cancer

Uploaded by

Copyright:

Available Formats

Biomedicine & Pharmacotherapy 163 (2023) 114822

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

The role of NF-κB in breast cancer initiation, growth, metastasis, and

1. Introduction solid tumors results in the development of inflammatory TME [35,36].

5.3. NF-κB inhibitors in BC therapy Acknowledgement

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.