Progesterone-action in the murine uterus and mammary gland requires steroid receptor coactivator 2: relevance to the human

10.2741/2340 ◽  
2007 ◽  
Vol 12 (8-12) ◽  
pp. 3640 ◽  
Author(s):  
Rodrigo Fernandez-Valdivia
Keyword(s):  
Mammary Gland ◽  
Steroid Receptor ◽  
Steroid Receptor Coactivator

scholarly journals Minireview: Steroid Receptor Coactivator-3: A Multifarious Coregulator in Mammary Gland Metastasis

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 19-25 ◽  
Author(s):  
John P. Lydon ◽  
Bert W. O'Malley
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Tumor Cell ◽  
Primary Tumor ◽  
Steroid Receptor ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Steroid Receptor Coactivator ◽  
Tumor Cell Motility

Abstract A member of the steroid receptor coactivator (SRC)/p160 family, SRC-3 acts as a coregulator for nuclear receptor (NR) and non-NR transcription factors. Such coregulator pleiotropy enables SRC-3 to influence a myriad of signaling networks that are essential for normal physiology and pathophysiology. Although SRC-3’s proliferative role in primary tumor formation in the mammary gland is well established, a role for this oncogenic coregulator in tumor cell motility and invasion has only recently been elucidated. In the nucleus, SRC-3 is required for the execution of the epithelial–mesenchymal transition, a programming step which endows an immotile cancer cell with motile and invasive characteristics. Nuclear SRC-3 is also essential for proteolytic breakdown of the extracellular matrix by matrix-metalloproteinases, a process which enables primary tumor cell invasion into the surrounding stroma. At the plasma membrane, however, a truncated isoform of SRC-3 (SRC-3Δ4) serves as a signaling adaptor for the epidermal growth factor→focal adhesion kinase→c-Src signal transduction pathway, a signaling cascade that is central to growth factor–induced cell migration and invasion. Together, these studies underscore a pivotal role for SRC-3 not only as a proto-oncogene but also as a prometastatic factor during the early steps in the invasion-metastasis cascade. Beyond furnishing critical mechanistic insights into SRC-3’s involvement in mammary tumor progression, these findings provide opportunities to develop new approaches for breast cancer diagnosis and intervention.

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

2006 ◽  
Vol 26 (17) ◽  
pp. 6571-6583 ◽  
Author(s):  
Atish Mukherjee ◽  
Selma M. Soyal ◽  
Rodrigo Fernandez-Valdivia ◽  
Martine Gehin ◽  
Pierre Chambon ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Embryo Implantation ◽  
Steroid Receptor ◽  
Ovarian Activity ◽  
Mouse Uterus ◽  
Steroid Receptor Coactivator ◽  
Mammary Morphogenesis ◽  
Uterine Function ◽  
And Function

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-2 flox/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.

scholarly journals Steroid Receptor Coactivator 2 is Required for Female Fertility and Mammary Morphogenesis: Insights from the Mouse, Relevance to the Human

2007 ◽  
Vol 5 (1) ◽  
pp. nrs.05011 ◽  
Author(s):  
Atish Mukherjee ◽  
Paula Amato ◽  
D. Craig Allred ◽  
Francesco J. DeMayo ◽  
John P. Lydon
Keyword(s):  
Mammary Gland ◽  
Gene Knockout ◽  
Embryo Implantation ◽  
Cell Types ◽  
Steroid Receptor ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Signaling Cascades ◽  
Steroid Receptor Coactivator ◽  
Female Reproductive Health

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.

scholarly journals Genetic Ablation of the Steroid Receptor Coactivator-Ubiquitin Ligase, E6-AP, Results in Tissue-Selective Steroid Hormone Resistance and Defects in Reproduction

2002 ◽  
Vol 22 (2) ◽  
pp. 525-535 ◽  
Author(s):  
Carolyn L. Smith ◽  
Darryll G. DeVera ◽  
Dolores J. Lamb ◽  
Zafar Nawaz ◽  
Yong-Hui Jiang ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Ubiquitin Ligase ◽  
Steroid Hormone ◽  
Steroid Receptor ◽  
Null Mouse ◽  
Wild Type ◽  
Male And Female ◽  
Genetic Ablation ◽  
Steroid Receptor Coactivator

ABSTRACT The E6-associated protein (E6-AP), although originally identified as a ubiquitin ligase, has recently been shown to function as a coactivator of steroid receptor-dependent gene expression in in vitro assays. In order to determine whether E6-AP acts as a coactivator in vivo, physiological parameters associated with male and female sex steroid action were assessed in the E6-AP null mouse. Gonadal size was reduced in E6-AP null male and female mice in comparison to wild-type controls in conjunction with reduced fertility in both genders. Consistent with this observation, defects in sperm production and function, as well as ovulation were observed. In comparison to wild-type controls, induction of prostate gland growth induced by testosterone and uterine growth by estradiol were significantly reduced. In contrast, estrogen and progesterone-stimulated growth of virgin mammary gland was not compromised by E6-AP ablation despite E6-AP expression in this tissue. This latter finding contrasts with the impaired estrogen and progesterone-induced mammary gland development observed previously for steroid receptor coactivator type 1 (SRC-1) and SRC-3 female knockout mice. Taken together, these results are consistent with a role for E6-AP in mediating a subset of steroid hormone actions in vivo. Nevertheless, differences observed between SRC and E6-AP knockout phenotypes indicate that these two families of steroid receptor coactivators are not functionally equivalent and supports the hypothesis that coactivators contribute to tissue-specific steroid hormone action.

scholarly journals The Steroid Receptor Coactivator-3 Is Required for Developing Neuroendocrine Tumor in the Mouse Prostate

2014 ◽  
Vol 10 (10) ◽  
pp. 1116-1127 ◽  
Author(s):  
Jean Ching-Yi Tien ◽  
Lan Liao ◽  
Yonghong Liu ◽  
Zhaoliang Liu ◽  
Dong-Kee Lee ◽  
...  
Keyword(s):  
Neuroendocrine Tumor ◽  
Steroid Receptor ◽  
Steroid Receptor Coactivator ◽  
Mouse Prostate
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