An epigenomic approach to therapy for tamoxifen-resistant breast cancer.

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.

• Authors: 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
• Journal: Cell research (Cell Res) Vol. 24 Issue 7 Pg. 809-19 (Jul 2014) ISSN: 1748-7838 [Electronic] England
• PMID: 24874954 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• (+)-JQ1 compound
• Azepines
• BRD3 protein, human
• BRD4 protein, human
• Cell Cycle Proteins
• ESR1 protein, human
• Estrogen Receptor alpha
• Nuclear Proteins
• RNA-Binding Proteins
• Repressor Proteins
• Transcription Factors
• Triazoles
• Tamoxifen
• Fulvestrant
• Estradiol
• Histone-Lysine N-Methyltransferase
• NSD2 protein, human

Topics

• Animals
• Azepines (therapeutic use)
• Breast Neoplasms (drug therapy, genetics)
• Cell Cycle Proteins
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Epigenomics
• Estradiol (analogs & derivatives, therapeutic use)
• Estrogen Receptor alpha (biosynthesis, physiology)
• Female
• Fulvestrant
• Histone-Lysine N-Methyltransferase (metabolism)
• Humans
• Mice
• Nuclear Proteins (physiology)
• RNA-Binding Proteins (physiology)
• Repressor Proteins (metabolism)
• Signal Transduction (drug effects)
• Tamoxifen (pharmacology, therapeutic use)
• Transcription Factors (physiology)
• Triazoles (therapeutic use)