期刊
CELL RESEARCH
卷 24, 期 7, 页码 809-819出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2014.71
关键词
epigenomic; tamoxifen; breast cancer
类别
资金
- DoD BCRP [BC122115, K01DK084209]
- Komen Promise Grant [R01HD07857]
- CPRIT [RP100348]
- Clayton Foundation
- ACS [RS-G1306101TBE]
- Dunn Foundation
- Breast Cancer Research Foundation
- [R01HD08188]
- [DOD-BC120894]
- [P30CA125123]
Tamoxifen has been a frontline treatment for estrogen receptor alpha (ER alpha)-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 ERa remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERa signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ER alpha signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ER alpha gene by the BET protein BRD3/4, and facilitates ER alpha gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ER alpha 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据