Tight Control of Steroid Receptor Coregulator-2 Expression Is Required to Maintain Normal Hormone Responsiveness in the Murine Endometrium.

Abstract

Steroid receptor coregulator-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 are known to selectively modulate the transactivational potency of both nuclear receptor (NR) and non-NR transcription factors, underscoring their potential for functional pleiotropy. Indeed, mouse studies have demonstrated that these coregulators exert diverse regulatory effects in vivo, ranging from modulating mammary morphogenesis to controlling metabolic homeostasis. Apart from normal physiology, however, deregulation of any one of these coregulators has been shown to be an important causal factor in the etiopathogenesis of many mammalian target tissues. In the case of the endometrium, clinical studies have revealed that SRC-2 (along with SRC-3) is significantly upregulated in endometrial biopsies from patients diagnosed with polycystic ovarian syndrome (PCOS). In many cases, the endometrium of PCOS patients display severe defects in functionality. Furthermore, expression of both coregulators is markedly increased in endometrial tissue exhibiting hyperplasia or cancer. Together, these findings suggest a causal link between deregulated expression of one or both of these coregulators and the emergence of these endometrial disorders. To test this supposition in the mouse, we recently developed an innovative cre-loxP engineering strategy to conditionally turn-on the expression of the human ortholog of SRC-2 (NCOA2) specifically in murine cell-types that are directly responsive to estrogen and progesterone exposure. At the gross morphological level, overexpression of human SRC-2 alone resulted in a marked enlargement of the uterus in the untreated adult virgin as compared to control siblings. At the cellular level, a persistent hyperproliferative state was detected in both the epithelial and stromal compartments of the endometrium. With ovariectomy followed by short-term treatment with estradiol, SRC-2 strikingly potentiated estradiol-induced uterine epithelial proliferation and stromal edema, suggesting a unique coregulator role for SRC-2 in the promotion of unopposed estrogen-action in this tissue. Because physiological levels of SRC-2 are essential for elaboration of the decidual response that normally occurs in the mouse and in cultured human endometrial stromal cells, our findings support the conclusion that cellular levels of SRC-2 require tight control to ensure normal steroid hormone responsiveness in the endometrium and to avoid unscheduled endometrial hyperplasia that can undermine normal functionality and predispose this tissue to tumorigenesis.This research was funded by National Institutes of Health grants (U54 HD-07495) and (CA-077530). (platform)