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Promotion of BRCA1-associated triple-negative breast cancer by ovarian hormones

Lee, Eva Y-HP

Current Opinion in Obstetrics and Gynecology: February 2008 - Volume 20 - Issue 1 - p 68–73
doi: 10.1097/GCO.0b013e3282f42237
Breast cancer: Edited by Anne O. Rodriguez

Purpose of review Mammary epithelial proliferation is controlled by the ovarian hormones estrogen and progesterone. Although BRCA1 (breast cancer 1, early onset) is ubiquitously expressed, women with BRCA1 mutations have a propensity to develop tumors in tissues sensitive to ovarian hormone. An understanding of the tissue-specific function of the BRCA1-encoded protein (BRCA1) provides additional insight that may improve cancer risk reduction in BRCA1 mutation carriers.

Recent findings Studies using mouse models have shown that BRCA1 regulates the abundance of progesterone receptor. The half-life of progesterone receptor is extended in cells harboring mutations in BRCA1. Reduced ubiquitination of progesterone receptor contributes to its stabilization and is correlated with increased cell proliferation in response to progesterone. Treatment of mutant mice with antiprogesterone prevents/delays tumor development. In vitro, BRCA1 and its interacting protein BARD1 (BRCA1-associated RING domain) serve as an ubiquitin ligase for the monoubiquitination of estrogen receptor-α, which may lead to alterations in estrogen receptor-α activity. Furthermore, the ubiquitin ligase activities of BRCA1/BARD1 may be determined by the ubiquitin-conjugating enzyme E2.

Summary BRCA1 exerts its tissue-specific function through the regulation of progesterone receptor and estrogen receptor-α. Interference with progesterone receptor, in addition to estrogen receptor-α, may be effective in reducing cancer risk in BRCA1 mutation carriers.

Departments of Biological Chemistry and Developmental & Cell Biology, University of California, Irvine, California, USA

Correspondence to Eva Lee, PhD, Departments of Biological Chemistry and Developmental & Cell Biology, University of California, Irvine, CA 92697-4037, USA Tel: +949 824 9766; fax: +949 824 9767; e-mail:

© 2008 Lippincott Williams & Wilkins, Inc.