FP06-4 Perturbation of Steroid Receptor Coactivator-2 Expression Levels Leads to Abnormal Steroid Hormone Responsiveness in the Murine Endometrium That Underpins a Severe Sub-Fertility Phenotype

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 381-386-Steroid Hormone Actions, Biosynthesis & Metabolism
Basic/Translational
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-381
Maria Magdalena Szwarc*, Ramakrishna Kommagani, San-Pin Wu, Sophia Y Tsai, Ming-Jer Tsai, Francesco J DeMayo and John P Lydon
Baylor College of Medicine, Houston, TX
Steroid receptor coactivator-2 (SRC-2) is a member of the p160/SRC family of coregulators, which also includes SRC-1 and SRC-3. Members of this coregulator class exert a wide-spectrum of physiological processes, ranging from mammary morphogenesis to metabolic homeostasis. Importantly, deregulation of SRC expression levels is a causal factor for many tissue pathologies in both human and mouse. In the case of the endometrium, clinical studies reveal that SRC-2 and SRC-3 levels are elevated in endometrial biopsies from patients diagnosed with polycystic ovary syndrome (PCOS). Significantly, the endometrium of PCOS patients displays severe defects in functionality, including increased endometrial cancer susceptibility and miscarriage rate. Elevated expression of both SRC-2 and SRC-3 has also been found in the hyperplastic and neoplastic endometrium. Collectively, these descriptive findings suggest a causal link between elevated expression of one or both coregulators and the emergence of these endometrial disorders.  To address this proposal further, we engineered a SRC-2 overexpressor (SRC-2: OE) mouse in which high levels of human SRC-2 expression are specifically targeted to cells that express the progesterone receptor. Long term-breeding studies, a decidual response assay, gonadotropin-induced superovulation, and measurement of serum hormone levels were conducted on SRC-2:OE mice to evaluate fertility status. Although ovulation and serum hormone levels are normal, six month breeding studies show that elevated levels of endometrial SRC-2 result in a severe subfertility defect. Importantly, an artificial decidual response assay revealed that the SRC-2:OE endometrium exhibits an impaired ability to undergo decidualization, an essential cellular process that enables embryo implantation to occur. The inability of the SRC-2:OE endometrium to decidualize is also reflected at the molecular level by a marked decrease in the induction of the decidual biomarkers, Follistatin, Wingless-related MMTV integration site 4, Bone morphogenetic protein 2 and Heart and neural crest derivatives expressed transcript 2. Furthermore, short- and long-term estradiol treatment reveals that perturbation of SRC-2 levels markedly potentiates estradiol-induced uterine epithelial hyperplasia, providing strong support for SRC-2 in the promotion of unopposed estrogen-action. We conclude that tight control of SRC-2—independent of changes in SRC-3 levels—is mandatory not only for normal endometrial functionality but also to prevent unscheduled endometrial hyperplasia which can lead to cancer.

Nothing to Disclose: MMS, RK, SPW, SYT, MJT, FJD, JPL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: National Institutes of Health (NIH) grants (U54 HD-07495) and (CA-077530).
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