Steroid Receptor Coactivator 2: An Essential Coregulator of Progestin-Induced Uterine and Mammary Morphogenesis
The importance of the progesterone receptor (PR) in transducing the progestin signal is firmly established in female reproductive and mammary gland biology; however, the coregulators preferentially recruited by PR in these systems have yet to be comprehensively investigated. Using an innovative genetic approach, which ablates gene function specifically in murine cell-lineages that express PR, steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) was shown to exert potent coregulator properties in progestin-dependent responses in the uterus and mammary gland. Uterine cells positive for PR (but devoid of SRC-2) led to an early block in embryo implantation, a phenotype not shared by knockouts for SRC-1 or SRC-3. In the case of the mammary gland, progestin-dependent branching morphogenesis and alveologenesis failed to occur in the absence of SRC-2, thereby establishing a critical coactivator role for SRC-2 in cellular proliferative programs initiated by progestins in this tissue. Importantly, the recent detection of SRC-2 in both human endometrium and breast suggests that this coregulator may provide a new clinical target for the future management of female reproductive health and/or breast cancer.
KeywordsMammary Gland Progesterone Receptor Recurrent Implantation Failure Flox Mouse Murine Mammary Gland
The technical assistance of Jie Li, Yan Ying, Jie Han, and Khauh Dao is gratefully acknowledged. We thank Drs. Pierre Chambon and Martine Gehin, Institut Clinique de la Souris, (ICS-IGBMC), BP10142, 67404 ILLKIRCH Cedex France, for providing the floxed SRC-2 mouse. This research was supported by NIH and private grants HD-42311 (F.J.D) and CA-77530 and Susan G. Komen Breast Cancer Research Program (J.P.L.).
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