An epigenomic approach to therapy for tamoxifen-resistant breast cancer

Qin Feng, Zheng Zhang, Martin J. Shea, Chad J. Creighton, Cristian Coarfa, Susan G. Hilsenbeck, Rainer Lanz, Bin He, Lei Wang, Xiaoyong Fu, Agostina Nardone, Yongcheng Song, James Bradner, Nicholas Mitsiades, Constantine S. Mitsiades, C. Kent Osborne, Rachel Schiff, Bert W. O'Malley

Research output: Contribution to journalArticle

111 Scopus citations

Abstract

Tamoxifen has been a frontline treatment for estrogen receptor alpha (ER)-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 ER remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ER signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ER signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ER gene by the BET protein BRD3/4, and facilitates ER gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ER 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.

Original languageEnglish (US)
Pages (from-to)809-819
Number of pages11
JournalCell Research
Volume24
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • breast cancer
  • epigenomic
  • tamoxifen

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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