Steroid receptor coactivator 2 is required for female fertility and mammary morphogenesis: insights from the mouse, relevance to the human.
Although the importance of the progesterone receptor (PR) to female reproductive and mammary gland biology is firmly established, the coregulators selectively co-opted by PR in these systems have not been clearly delineated. A selective gene-knockout approach applied to the mouse, which abrogates gene function only in cell types that express PR, recently disclosed steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) to be an indispensable coregulator for uterine and mammary gland responses that require progesterone. Uterine cells positive for PR (but devoid of SRC-2) were found to be incapable of facilitating embryo implantation, a necessary first step toward the establishment of the materno-fetal interface. Importantly, such an implantation defect is not exhibited by knockouts for SRC-1 or SRC-3, underscoring the unique coregulator importance of SRC-2 in peri-implantation biology. Moreover, despite normal levels of PR, SRC-1 and SRC-3, progesterone-dependent branching morphogenesis and alveologenesis fails to occur in the murine mammary gland in the absence of SRC-2, thereby establishing a critical coregulator role for SRC-2 in signaling cascades that mediate progesterone-induced mammary epithelial proliferation. Finally, the recent detection of SRC-2 in the human endometrium and breast suggests that this coregulator may represent a new clinical target for the future management of female reproductive health and/or breast cancer.
Mukherjee
Atish
A
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Amato
Paula
P
Allred
D Craig
DC
DeMayo
Francesco J
FJ
Lydon
John P
JP
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000502:physiology*; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis / Q000502:physiology*; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism*
D051958:Nuclear Receptor Coactivator 2