National Centers for Translational Research in Reproduction and Infertility
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The ERbeta/SRC-1 Isoform Complex drives Endometriosis Progression

Bert W. O’Malley, M.D.
Tom Thompson Distinguished Service Professor
Professor and Chair
Department of Molecular and Cellular Biology
Baylor College of Medicine
One Baylor Plaza
DeBakey M613, MS:BCM502
Houston, TX 77030
Phone: 713-798-6205
Fax: 713-798-5599
E-mail: berto@bcm.edu

 

Endometrial cells can escape from the lining of the uterus and flourish in ectopic sites, resulting in endometriosis, a pathology that results in severe pelvic pain and infertility in up to 15% of women. Estrogen is considered a key driver in the progression of this disease and recent studies suggest distinct roles for estrogen receptor-a (ERa) and -p (ERp); however, the specific roles of either receptor in endometriosis progression are not elucidated. Notably, endometriotic tissues have a much higher ratio of ERp to ERa compared to normal endometrium. In addition, preliminary data from our laboratory have revealed that ERp plays an essential role in ectopic lesion growth because ectopic lesion expansion is suppressed in ERp knockout mice, and greatly enhanced ectopic lesion volume is noted in mice that overexpress ERp in the endometrium. Therefore, our data strongly support a key role for ERp in the pathogenesis of endometriosis. We recently published that the steroid receptor coactivator-1 (SRC-1) protein can be proteolytically cleaved into an isoform that is a major contributor to the pathogenesis of endometriosis (Nat. Med., 2012). Interestingly, this SRC-1 isoform interacts with ERp in endometriotic tissue and overexpression of one or both proteins can prevent tumor necrosis factor alpha caspase 8 mediated apoptosis of endometrial tissue autotransplanted at an ectopic site. In this way, ectopic lesions are stabilized and maintained. Here, we will codify the molecular mechanisms by which the SRC-1 isoform/ERp complex enhances the growth of ectopic endometrial cells. Because both SRC-1 and ERp are tractable molecular targets for small molecule inhibitors, we also wilt test novel therapeutic approaches that target these two key targets in preclinical models of endometriosis. Already, we have undertaken ultra-high throughput screening approaches to identify potential inhibitors of the full-length SRC-1. We plan to use information from these screens to identify agents that also inhibit the activity of the SRC-1 proteolytic isoform. A key component of the research proposed herein is to develop an important and needed ‘first-in-class’ drug with a ‘unique mechanism of action’ to target the SRC-1 isoform that can be used alone or in combination with ERp antagonists to prevent and/or treat women at high risk for endometriosis