Steroid Receptor Coactivator 2 Is Critical for Progesterone-Dependent Uterine Function and Mammary Morphogenesis in the Mouse

Abstract

Although the essential involvement of the progesterone receptor (PR) in female reproductive tissues is firmly established, the coregulators preferentially enlisted by PR to mediate its physiological effects have yet to be fully delineated. To further dissect the roles of members of the steroid receptor coactivator (SRC)/p160 family in PR-mediated reproductive processes in vivo, state-of-the-art cre-loxP engineering strategies were employed to generate a mouse model (PR Cre/؉ SRC-2 flox/flox ) in which SRC-2 function was abrogated only in cell lineages that express the PR. Fertility tests revealed that while ovarian activity was normal, PR Cre/؉ SRC-2 flox/flox mouse uterine function was severely compromised. Absence of SRC-2 in PR-positive uterine cells was shown to contribute to an early block in embryo implantation, a phenotype not shared by SRC-1 or -3 knockout mice. In addition, histological and molecular analyses revealed an inability of the PR Cre/؉ SRC-2 flox/flox mouse uterus to undergo the necessary cellular and molecular changes that precede complete P-induced decidual progression. Moreover, removal of SRC-1 in the PR Cre/؉ SRC-2 flox/flox mouse uterus resulted in the absence of a decidual response, confirming that uterine SRC-2 and -1 cooperate in P-initiated transcriptional programs which lead to full decidualization. In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR Cre/؉ SRC-2flox/flox mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR. We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function.The progesterone (P) receptor (PR) knockout (KO) mouse, in which both isoforms (PR-A and -B) were ablated, highlighted the importance of P as a pleiotropic coordinator of female reproductive biology (24). Abrogation of PR not only undermined uterine morphogenesis and function but also severely compromised the normal operation of the hypothalamopituitary-ovarian axis. These studies further revealed a crucial role for P signaling in mammary epithelial proliferation, an essential cellular event that enables parity-induced mammary morphogenesis to manifest in the adult. In addition, the PR KO mouse exhibited a marked reduction in mammary tumor susceptibility (25), revealing a dual role for PR-mediated epithelial proliferation in mammary tumorigenesis, as well as in normal mammary morphogenesis.Apart from providing new cellular principles by which P influences proliferative and differentiative programs obligate for target tissue morphogenesis and tumorigenesis, two important questions have emerged from these studies regarding PR's mechanism of action for a given target tissue: (i) what are the signature molecular effectors that transduce the P signal to an appropriate physiological response, and (ii) which coregulators (coactivators and/or corep...

Interaction of steroid receptor coactivators and estrogen receptors in the human placenta

“…SRCs interact with ER and enhance estrogen signals. Coactivators such as SRCs are fundamental to the proper function of reproductive events such as fertility (Mukherjee et al 2007), uterine growth, blastocyst implantation (Mukherjee et al 2006), and mammary gland development (Xu et al 2000). The pleiotropic actions of SRCs make them attractive candidates as biomarkers for a multitude of pathologies.…”

Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium

“…P 4 signaling inhibits the estrogen signaling pathways in the uterus (Hsueh et al 1975) and this inhibitory relationship involving both hormone pathways orchestrate the regulatory mechanisms required for endometrial receptivity and embryo implantation. Amongst the regulated transcripts in the mid-secretory endometrium from women with mifepristone administration we found several genes involved in the P 4 signaling axis including modulators and effectors with down regulation of NCOA2 (SRC-2, (Mukherjee et al 2006, Jeong et al 2007), IHH (Matsumoto et al 2002, Takamoto et al 2002, ERRFI1 (MIG6, (Kim et al 2010)) PTCH1 (Lee et al 2006) and DKK1 ; and up-regulation of ESR1 (Curtis et al 1999), PRA (Conneely & Lydon 2000), FKBP5 (Tranguch et al 2005), FOXO1A (Kim et al 2005), KLF9 (Simmen et al 2004) and PTGS1 (Wang et al 2004).…”

Histone Modification and Breast Cancer

“…By regulating a broad range of gene expression controlled by NRs and non-NR transcription factors, NCOAs regulate diverse events in the development of breast cancer. Either NCOA1 or NCOA2 deficiency can reduce ductal side branching and alveologenesis in the mammary gland (Xu et al, 1998;Mukherjee et al, 2006), and NCOA3 −/− mice show growth retardation, delayed puberty, reduced female reproductive function and blunted mammary gland development (Xu et al, 2000). In normal human breast, the levels of the three NCOA proteins in epithelial cells are usually low or undetectable (Hudelist et al, 2003).…”