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Cell Res. 2014 Jul;24(7):809-19. doi: 10.1038/cr.2014.71. Epub 2014 May 30.

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

Author information

1
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
2
Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
3
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
4
1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Department of Medicine-Hematology & Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
5
1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA [3] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
6
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
8
1] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA [2] Department of Medicine-Hematology & Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
9
1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA [2] Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.

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.

PMID:
24874954
PMCID:
PMC4085766
DOI:
10.1038/cr.2014.71
[Indexed for MEDLINE]
Free PMC Article

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