Background Prostate cancer is the second most frequently diagnosed cancer in men. Animal models t... more Background Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat. Methods The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits. Results Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. Conclusion The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of chemoprevention, intervention, regression, and therapeutic studies using prostate cancer rodent models.
Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and... more Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anti-cancer activities. We hypothesized that resveratrol would exert a chemopreventive effect against prostate cancer via regulation of sex steroid receptor and growth factor signaling pathways. In the current study, Transgenic Adenocarcinoma Mouse Prostate (TRAMP) males were fed resveratrol (625 mg resveratrol/kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at five weeks of age. Mechanisms of action and histopathology studies were conducted at 12 and 28 weeks of age, respectively. Resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-fold. In the dorsolateral prostate (DLP), resveratrol significantly inhibited cell proliferation, increased androgen receptor (AR), estrogen receptor-β (ER-β), and insulin-like growth factor-1 receptor (IGF-1R), and significantly decreased IGF-1, and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate (VP), resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter IGF-1R and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone (DHT), and sex hormone binding globulin (SHBG) concentrations and SV-40 Tag expression in the prostate were not altered in resveratroltreated mice. Total resveratrol concentration in the blood serum of 12 week old mice treated for three weeks with 625 mg resveratrol/kg diet was 52 ± 18 nM. The decrease in cell proliferation and the potent growth factor, IGF-1, the down-regulation of downstream effectors, phospho-ERKs 1 and 2, and the increase in the putative tumor by guest on September 20, 2013 http://carcin.oxfordjournals.org/ Downloaded from 3 suppressor, ER-β, provide a biochemical basis for resveratrol suppressing prostate cancer development. Introduction With an anticipated 27,050 deaths in 2007, prostate cancer is second only to lung cancer in cancer-related deaths among men [1]. In the prostate, pre-neoplastic lesions start to develop early in life. It has been reported that men of 20-40 years develop low-grade prostatic intraepithelial neoplasia (PIN), with a frequency of 9%, 16%, and 26%, respectively [2]
1. Almost 200,000 men and women in the United States will be diagnosed with prostate and breast c... more 1. Almost 200,000 men and women in the United States will be diagnosed with prostate and breast cancers, respectively, this year alone. It has become increasingly clear that environmental exposures, including diet, influence the risk of both breast and prostate cancers. 2. Two natural polyphenols that have received much interest in the field of cancer prevention are genistein, an isoflavone component of soy, and resveratrol, a phytoalexin found in red grapes and red wine. Epidemiological and in vitro laboratory data suggest that these polyphenols may protect against breast and prostate cancers. 3. Using in vivo rodent models of breast and prostate cancers, our lab and others have shown that genistein and resveratrol, administered alone or in combination, can suppress both breast and prostate carcinogenesis. 4. Genistein, at concentrations resulting in serum levels comparable to humans on a high soy diet, suppressed mammary tumor multiplicity through enhanced mammary gland maturation and a reduction in the targets of mammary carcinogens. Genistein also reduced the incidence of aggressive prostate tumors in a transgenic mouse model of prostate cancer. 5. Resveratrol, administered in the diet, suppressed mammary tumor multiplicity and increased tumor latency. Reductions in mammary epithelial cell proliferation and increased apoptosis help to explain these mammary protective effects. Resveratrol was also able to reduce the incidence of poorly differentiated prostate tumors through modulation of cell proliferation and critical growth factor pathways in the rodent prostate. 6. Chemoprevention of both breast and prostate cancers with combinational genistein and resveratrol treatments was also demonstrated. Both resveratrol and genistein, alone and in combination, were effective at suppressing breast and prostate carcinogenesis using in vivo models.
Background Prostate cancer is the second most frequently diagnosed cancer in men. Animal models t... more Background Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat. Methods The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits. Results Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. Conclusion The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical trials and aids in the rational design of chemoprevention, intervention, regression, and therapeutic studies using prostate cancer rodent models.
Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and... more Resveratrol, a natural polyphenolic phytochemical, has been reported to act as an antioxidant and provide anti-cancer activities. We hypothesized that resveratrol would exert a chemopreventive effect against prostate cancer via regulation of sex steroid receptor and growth factor signaling pathways. In the current study, Transgenic Adenocarcinoma Mouse Prostate (TRAMP) males were fed resveratrol (625 mg resveratrol/kg AIN-76A diet) or phytoestrogen-free, control diet (AIN-76A) starting at five weeks of age. Mechanisms of action and histopathology studies were conducted at 12 and 28 weeks of age, respectively. Resveratrol in the diet significantly reduced the incidence of poorly differentiated prostatic adenocarcinoma by 7.7-fold. In the dorsolateral prostate (DLP), resveratrol significantly inhibited cell proliferation, increased androgen receptor (AR), estrogen receptor-β (ER-β), and insulin-like growth factor-1 receptor (IGF-1R), and significantly decreased IGF-1, and phospho-extracellular regulating kinase 1 (phospho-ERK 1). In the ventral prostate (VP), resveratrol significantly reduced cell proliferation and phospho-ERKs 1 and 2, but did not significantly alter IGF-1R and IGF-1. Serum total testosterone, free testosterone, estradiol, dihydrotestosterone (DHT), and sex hormone binding globulin (SHBG) concentrations and SV-40 Tag expression in the prostate were not altered in resveratroltreated mice. Total resveratrol concentration in the blood serum of 12 week old mice treated for three weeks with 625 mg resveratrol/kg diet was 52 ± 18 nM. The decrease in cell proliferation and the potent growth factor, IGF-1, the down-regulation of downstream effectors, phospho-ERKs 1 and 2, and the increase in the putative tumor by guest on September 20, 2013 http://carcin.oxfordjournals.org/ Downloaded from 3 suppressor, ER-β, provide a biochemical basis for resveratrol suppressing prostate cancer development. Introduction With an anticipated 27,050 deaths in 2007, prostate cancer is second only to lung cancer in cancer-related deaths among men [1]. In the prostate, pre-neoplastic lesions start to develop early in life. It has been reported that men of 20-40 years develop low-grade prostatic intraepithelial neoplasia (PIN), with a frequency of 9%, 16%, and 26%, respectively [2]
1. Almost 200,000 men and women in the United States will be diagnosed with prostate and breast c... more 1. Almost 200,000 men and women in the United States will be diagnosed with prostate and breast cancers, respectively, this year alone. It has become increasingly clear that environmental exposures, including diet, influence the risk of both breast and prostate cancers. 2. Two natural polyphenols that have received much interest in the field of cancer prevention are genistein, an isoflavone component of soy, and resveratrol, a phytoalexin found in red grapes and red wine. Epidemiological and in vitro laboratory data suggest that these polyphenols may protect against breast and prostate cancers. 3. Using in vivo rodent models of breast and prostate cancers, our lab and others have shown that genistein and resveratrol, administered alone or in combination, can suppress both breast and prostate carcinogenesis. 4. Genistein, at concentrations resulting in serum levels comparable to humans on a high soy diet, suppressed mammary tumor multiplicity through enhanced mammary gland maturation and a reduction in the targets of mammary carcinogens. Genistein also reduced the incidence of aggressive prostate tumors in a transgenic mouse model of prostate cancer. 5. Resveratrol, administered in the diet, suppressed mammary tumor multiplicity and increased tumor latency. Reductions in mammary epithelial cell proliferation and increased apoptosis help to explain these mammary protective effects. Resveratrol was also able to reduce the incidence of poorly differentiated prostate tumors through modulation of cell proliferation and critical growth factor pathways in the rodent prostate. 6. Chemoprevention of both breast and prostate cancers with combinational genistein and resveratrol treatments was also demonstrated. Both resveratrol and genistein, alone and in combination, were effective at suppressing breast and prostate carcinogenesis using in vivo models.
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