An epigenomic approach to therapy for tamoxifen-resistant breast cancer
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Author
Feng, Qin
Zhang, Zheng
Shea, Martin J
Creighton, Chad J
Coarfa, Cristian
Hilsenbeck, Susan G
Lanz, Rainer
He, Bin
Wang, Lei
Fu, Xiaoyong
Nardone, Agostina
Song, Yongcheng
Mitsiades, Nicholas
Osborne, C Kent
Schiff, Rachel
O'Malley, Bert W
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https://doi.org/10.1038/cr.2014.71Metadata
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Feng, Q., Z. Zhang, M. J. Shea, C. J. Creighton, C. Coarfa, S. G. Hilsenbeck, R. Lanz, et al. 2014. “An epigenomic approach to therapy for tamoxifen-resistant breast cancer.” Cell Research 24 (7): 809-819. doi:10.1038/cr.2014.71. http://dx.doi.org/10.1038/cr.2014.71.Abstract
Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085766/pdf/Terms of Use
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