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LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer

Oncogene volume 35, pages 2746–2755 (2016)Cite this article

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Abstract

Tamoxifen, an estrogen receptor (ER) antagonist, is the mainstay treatment of breast cancer and the development of resistance represents a major obstacle for a cure. Although long non-coding RNAs such as HOTAIR have been implicated in breast tumorigenesis, their roles in chemotherapy resistance remain largely unknown. In this study, we report that HOTAIR (HOX antisense intergenic RNA) is upregulated in tamoxifen-resistant breast cancer tissues compared to their primary counterparts. Mechanistically, HOTAIR is a direct target of ER-mediated transcriptional repression and is thus restored upon the blockade of ER signaling, either by hormone deprivation or by tamoxifen treatment. Interestingly, this elevated HOTAIR increases ER protein level and thus enhances ER occupancy on the chromatin and potentiates its downstream gene regulation. HOTAIR overexpression is sufficient to activate the ER transcriptional program even under hormone-deprived conditions. Functionally, we found that HOTAIR overexpression increases breast cancer cell proliferation, whereas its depletion significantly impairs cell survival and abolishes tamoxifen-resistant cell growth. In conclusion, the long non-coding RNA HOTAIR is directly repressed by ER and its upregulation promotes ligand-independent ER activities and contributes to tamoxifen resistance.

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Acknowledgements

Bioinformatic analysis was supported by the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University, which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. This work was supported by the the US Department of Defense W81XWH-13-1-0319 (to JY) and the Research Scholar Award RSG-12-085-01 (to JY) from the American Cancer Society. JK was supported in part by the National Institutes of Health Training Program in Oncogenesis and Developmental Biology (T32 CA080621), and YAY was supported in part by the National Institutes of Health/National Cancer Institute training grant T32 CA009560.

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Author notes

  1. X Xue and Y A Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Thoracic Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China

    X Xue

  2. Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    X Xue, Y A Yang, A Zhang, K-W Fong, J Kim, B Song, S Li, J C Zhao & J Yu

  3. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    J Yu

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Xue, X., Yang, Y., Zhang, A. et al. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene 35, 2746–2755 (2016). https://doi.org/10.1038/onc.2015.340

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