Volume 24, No 7, Jul 2014

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 24 Issue 7, July 2014: 809-819   |  Open Access

ORIGINAL ARTICLES

An epigenomic approach to therapy for tamoxifen-resistant breast cancer

Qin Feng¹, Zheng Zhang¹, Martin J Shea², Chad J Creighton³, Cristian Coarfa³, Susan G Hilsenbeck², Rainer Lanz¹, Bin He^1,4, Lei Wang¹, Xiaoyong Fu^1,2,3, Agostina Nardone^1,2,3, Yongcheng Song⁵, James Bradner⁶, Nicholas Mitsiades^3,4, Constantine S Mitsiades⁶, C Kent Osborne^1,2,3, Rachel Schiff^1,2,3 and Bert W O Malley^1,3

¹Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
²Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
³Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
⁴Department of Medicine-Hematology & Oncology, Baylor College of Medicine, Houston, TX 77030, USA
⁵Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA
⁶Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA Correspondence: Bert W O Malley,(E-mail: berto@bcm.edu)

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.

10.1038/cr.2014.71

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