An epigenomic approach to therapy for tamoxifen-resistant breast cancer

被引：149

作者：

Feng, Qin ^{[1
]}

Zhang, Zheng ^{[1
]}

Shea, Martin J. ^{[2
]}

Creighton, Chad J. ^{[3
]}

Coarfa, Cristian ^{[3
]}

Hilsenbeck, Susan G. ^{[2
]}

Lanz, Rainer ^{[1
]}

He, Bin ^{[1
,4
]}

Wang, Lei ^{[1
]}

Fu, Xiaoyong ^{[1
,2
,3
]}

Nardone, Agostina ^{[1
,2
,3
]}

Song, Yongcheng ^{[5
]}

Bradner, James ^{[6
]}

Mitsiades, Nicholas ^{[3
,4
]}

Mitsiades, Constantine S. ^{[6
]}

Osborne, C. Kent ^{[1
,2
,3
]}

Schiff, Rachel ^{[1
,2
,3
]}

O'Malley, Bert W. ^{[1
,3
]}

机构：

[1] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[2] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA

[3] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Med Hematol & Oncol, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA

[6] Harvard Univ, Dana Farber Canc Inst, Dept Med, Dept Med Oncol,Med Sch, Boston, MA 02215 USA

来源：

CELL RESEARCH | 2014年 / 24卷 / 07期

关键词：

epigenomic; tamoxifen; breast cancer; BET BROMODOMAIN INHIBITION; ACUTE MYELOID-LEUKEMIA; ENDOCRINE RESISTANCE; LUNG ADENOCARCINOMA; HISTONE H3; LYSINE; 36; C-MYC; RECEPTOR; CELLS; BRD4;

D O I：

10.1038/cr.2014.71

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：809 / 819

页数：11

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