ReviewThe biology of progesterone receptor in the normal mammary gland and in breast cancer
Highlights
► This paper reviews the role of progesterone (P4) in mammary gland development. ► In the mouse P4 controls luminal epithelial proliferation and stem cell expansion. ► These P4 effects are mediated by a RANKL paracrine signaling pathway. ► Dysregulation of RANKL signaling promotes hormone-dependent mouse mammary tumors. ► Whether RANKL has a role in hormone-dependent human breast cancer is unknown. ► PR has tumor suppressor activity at later stages of breast cancer progression.
Introduction
The mammary gland is a hormonally responsive target tissue that develops predominantly after birth, and is capable of undergoing sequential cycles of development through pregnancy, lactation and involution. Because of common developmental and hormonal response features, the mouse mammary gland has served as an experimental system for modeling normal human breast and breast cancer (Conneely et al., 2003). Progesterone (P4) is a key cycling ovarian steroid hormone that is highest in the luteal phase and has a major role to promote glandular differentiation of the endometrium. P4 is also sustained at high levels during pregnancy and is required for maintenance of pregnancy (Anderson and Clarke, 2004, Graham and Clarke, 1997, Howard and Gusterson, 2000, Silberstein et al., 1996). Experimental manipulation of mouse ovarian function has demonstrated the importance of P4 for proliferation and ductal side branching of the mammary gland during puberty and for alveologenesis during pregnancy (Graham and Clarke, 1997). The essential nature of the P4 signaling axis for mammary gland development has also been defined through studies of the progesterone receptor (PR) knockout mouse (PRKO) (Lydon et al., 1995). PR is a member of the nuclear hormone receptor family of ligand-dependent transcription factors that functions by binding to specific target genes either through cis-acting progesterone response elements (PREs) or by tethering to other DNA bound transcription factors. DNA bound receptor recruits co-regulatory proteins that affect chromatin structure and rates of gene transcription (Bulynko and O’Malley, 2010, Kastner et al., 1990, Li and O’Malley, 2003, Mangelsdorf et al., 1995). In addition to its action as a transcription factor, a subpopulation of PR functions outside of the nucleus to mediate rapid (minutes) P4 induced activation of protein phosphorylation signaling cascades (Ballare et al., 2003, Boonyaratanakornkit et al., 2001, Edwards, 2005). In both humans and mice, PR is expressed as two isoforms, PR-A and PR-B that have identical ligand–binding (LBD) and DNA-binding domains (DBD) and differ only in truncation of the amino-terminal domain (NTD) in PR-A (Aupperlee et al., 2005, Aupperlee and Haslam, 2007, Kastner et al., 1990, Li and O’Malley, 2003, Mangelsdorf et al., 1995, Mulac-Jericevic et al., 2000, Shyamala et al., 1998). In human breast cancer cell lines PR-B is a stronger transcriptional activator than PR-A, and the two isoforms have been characterized to regulate different but overlapping subsets of target genes (Graham et al., 2005, Jacobsen et al., 2003). Also, the proliferative effect of P4 in breast cancer cells is mediated primarily by PR-B (Boonyaratanakornkit et al., 2007, Daniel et al., 2009, Faivre et al., 2008, Jacobsen et al., 2003, Skildum et al., 2005). Based on phenotypes of PR isoform selective knockout mice, PR-B is more important for the proliferative responses to P4 in the mammary epithelium, while ovarian and uterine development and function rely primarily on PR-A (Mulac-Jericevic et al., 2000, Mulac-Jericevic et al., 2003). Distinct functions in the mouse in vivo are due in part to differential expression of PR-A and PR-B during development of the mammary gland and in cell compartments of the uterus (Aupperlee et al., 2005, Aupperlee and Haslam, 2007, Kariagina et al., 2007, Mote et al., 2006). This paper reviews the role of P4 and PR in normal mammary gland development, focusing primarily on the mouse model, and in breast cancer based on studies of mouse and human models.
Section snippets
Epithelial cell autonomous actions of PR in the mammary gland
During post-natal development and puberty the mouse mammary gland ductal cap cells proliferate leading to elongation of the ductal tree into the fat pad (Anderson and Clarke, 2004, Graham and Clarke, 1997, Scarpin et al., 2009). In the PRKO mouse, ductal elongation is similar to that of the wild type mouse, establishing that P4/PR signaling is not required for ductal elongation (Lydon et al., 1995). The phenotpye of estrogen receptor alpha (ERα) knockout mice has established the requirement of
Progesterone regulation of cell proliferation and morphogenesis by paracrine pathways
Based on immunohistochemistry PR is exclusively expressed in the epithelial cell compartment of mammary gland ducts with no evidence of expression in myoepithelial cells or stroma (Grimm et al., 2002, Ismail et al., 2003, Shyamala et al., 1997, Shyamala et al., 2002, Silberstein et al., 1996). PR is uniformly expressed in epithelial cells in juvenile mammary gland ducts but switches to a heterogeneous pattern during puberty and in the adult. In the adult, PR is expressed in ∼40% of cells and PR
Paracrine and other mediators of P4/PR signaling in the mouse mammary gland
Several downstream targets have been implicated as effectors of P4 induced cellular proliferation and morphogenesis including Wnt4, amphiregulin, calcitonin, inhibitor of DNA binding 4 (Id4) and receptor activator of nuclear factor κB ligand (RANKL). These genes are known to be involved in proliferation and/or morphogenesis and are induced by P4 in the mammary gland in a manner dependent on PR (Beleut et al., 2010, Brisken et al., 2000, Fernandez-Valdivia et al., 2008, Gavin and McMahon, 1992,
P4/PR suppression of differentiation during pregnancy
In mid-to-late pregnancy, progesterone inhibits milk protein production and closure of tight junctions until parturition (Neville et al., 2002). Tight junctions of the mammary epithelium remain open during pregnancy and their closure during lactation is important to prevent reflux of accumulated milk into the ductal lumen and interstitial spaces (Neville et al., 2002, Nguyen et al., 2001). In the mouse, a precipitous decline in circulating P4 at parturition is associated with increased milk
Crosstalk between prolactin/Stat5 and progesterone/PR signaling pathways
Both P4 and prolactin (PRL) are required for epithelial cell expansion and alveologenesis. Endocrine ablation and gene knockout studies have shown that neither hormone alone is sufficient, and PRKO and PRL receptor knockout (PRLRKO) mice exhibit a similar phenotype suggesting crosstalk between P4 and PRL signaling pathways (Barash, 2006, Bole-Feysot et al., 1998, Brisken and Rajaram, 2006, Fendrick et al., 1998, Goffin and Kelly, 1997, Hennighausen and Robinson, 2008). Gene microarray analysis
P4/PR signaling in mouse mammary gland vs. normal human breast
Segregation of ER/PR positive from steroid hormone induced proliferative cells appears to be conserved in the human breast. As determined by immunohistochemistry, the patterning of ER/PR expression in human breast tissue is similar to that of the mouse mammary gland. ER and PR expression is non-uniform and the two steroid receptors colocalize largely in non-proliferating luminal epithelial cells that are nearby ER/PR negative proliferating cells (Anderson et al., 1998, Anderson, 2002, Anderson
Progesterone regulated RANKL signaling in mammary tumorigenesis
A hallmark of pre-neoplastic lesions and mammary tumors is an increase in the proportion of proliferating ER/PR positive cells, suggesting a switch from a paracrine to an autocrine mode of regulation by steroid hormones (Anderson, 2002, Brisken, 2002, Brisken and Rajaram, 2006, Rosen, 2003). In mouse models of hormone-dependent mammary tumors, an increase in the percentage of proliferating ER/PR positive cells is associated with hyperplasias and development of ductal carcinoma in situ (DCIS) (
Progesterone/PR signaling in human breast cancer
The estrogen/ER signaling axis is a major player in stimulating growth and progression of the luminal subtype human breast cancers and indeed targeted anti-estrogen therapies have been successful in treatment of ER positive tumors (Bast et al., 2001). Early on, progesterone was assumed to be of little consequence in the etiology or progression of breast cancer, in part due to its well established role to inhibit proliferation of the uterine endometrium and to promote differentiation of uterine
Conclusion
Much of our understanding of the biology of PR in the normal mammary gland and the role of progesterone/PR signaling in tumor progression comes from studies with mouse experimental models. In part due to lack of suitable experimental models, uncertainties remain concerning the mechanism of action of progesterone and PR in the normal human breast and in the etiology and progression of human breast cancer. Available data indicates that progesterone as a proliferative hormone is a risk factor for
Acknowledgements
Some of the work described in this review was supported in part by NIH Grants DK049030 and HD038129 (DPE) and NIH Training Grant T32 HD007165 (AEO).
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