Challenges to defining a role for progesterone in breast cancer - PubMed (original) (raw)

Review

Challenges to defining a role for progesterone in breast cancer

Carol A Lange. Steroids. 2008 Oct.

Abstract

Progesterone is an ovarian steroid hormone that is essential for normal breast development during puberty and in preparation for lactation. The actions of progesterone are primarily mediated by its high affinity receptors, including the classical progesterone receptor (PR) -A and -B isoforms, located in diverse tissues such as the brain where progesterone controls reproductive behavior, and the breast and reproductive organs. Progestins are frequently prescribed as contraceptives or to alleviate menopausal symptoms, wherein progestin is combined with estrogen as a means to block estrogen-induced endometrial growth. Estrogen is undisputed as a potent breast mitogen, and inhibitors of the estrogen receptor (ER) and estrogen producing enzymes (aromatases) are effective first-line cancer therapies. However, PR action in breast cancer remains controversial. Herein, we review existing evidence from in vitro and in vivo models, and discuss the challenges to defining a role for progesterone in breast cancer.

PubMed Disclaimer

Figures

Figure 1. Mammary gland structure

A. Acini, located at the ends of ducts in the adult mammary gland, are the functional units of the lactating mammary gland. Luminal epithelial cells (apical) exist as polar cells in contact with myoepithelial cells (basal). Epithelial cell populations are separated from the stroma by a basement membrane. B. Steroid hormone receptor positive (ER+/PR+) cells occur adjacent to proliferating cells in the normal mammary gland. Communication (paracrine signaling) between the epithelial and stromal compartments mediates proliferation of ER/PR negative cells. Early events during breast cancer development may mediate switching from paracrine to autocrine mechanisms of proliferation in ER+/PR+ cells.

Figure 1. Mammary gland structure

Figure 2. Progesterone receptor-dependent integrated actions

A. Ligand activated PR-B and PR-A transcription factors contain a hormone binding domain (HBD), hinge region (H), DNA-binding domain (DBD), and amino terminus. Activation functions (AFs) represent the sites of co-regulator interaction required for transcription. Serines 294, 345, and 400 are regulatory sites that are phosphorlyated in response to progestins and/or mitogenic signaling pathways that modify PR function. B. Phosphorylation (P) of specific sites in PR couples multiple receptor functions. 1. Ligand-binding mediates dissociation of heat-shock proteins (hsps) and nuclear accumulation of PR. 2. Nuclear PRs regulate gene expression via the classical (PRE-dependent) pathway; phosphorylated PR recruit regulatory molecules that are phospho-proteins, and may function in one or more inter-connected processes (transcription, localization, and turnover). 3. PR and growth factors activate MAPKs via a c-Src kinase-dependent pathway, and this may result in positive regulation of PR transcriptional activity via “feed-back” regulation (i.e. direct phosphorylation of liganded PR or co-activators), occurring in both the absence and presence of ligands and on PRE-containing or other PR-regulated gene promoters. 4. Activation of MAPKs by PR provides for regulation of genes whose promoters do not contain PREs and are otherwise independent of PR-transcriptional activities but utilize PR-activated MAPKs. 5. In response to progestins, c-Src and MAPK-dependent phosphorylation of PR Ser345 mediates tethering to Sp1 and selective regulation of growth promoting genes via Sp1 sites (p21, EGFR).

Figure 2. Progesterone receptor-dependent integrated actions

References

1. Hewitt SC, Korach KS. Progesterone action and responses in the alphaERKO mouse. Steroids. 2000;65(10–11):551–557. - PubMed
1. Feng Y, Manka D, Wagner KU, Khan SA. Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci U S A. 2007;104(37):14718–14723. - PMC - PubMed
1. Mulac-Jericevic B, Conneely OM. Reproductive tissue selective actions of progesterone receptors. Reproduction. 2004;128(2):139–146. - PubMed
1. Haslam SZ, Counterman LJ, Nummy KA. Effects of epidermal growth factor, estrogen, and progestin on DNA synthesis in mammary cells in vivo are determined by the developmental state of the gland. J Cell Physiol. 1993;155(1):72–78. - PubMed
1. Ruan W, Monaco ME, Kleinberg DL. Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action. Endocrinology. 2005;146(3):1170–1178. - PubMed

Challenges to defining a role for progesterone in breast cancer - PubMed (original) (raw)