Normal breast development requires ERα, PRs, and growth factors. Estrogen stimulates ductal elongation, and progestins induce ductal sidebranching and alveologenesis [22
]. Epidermal growth factor (EGF), in addition to promoting the proliferation of terminal end-buds, augments estrogen-induced ductal outgrowth and progesterone-induced sidebranching [23
]. Indeed, estrogen induces PR isoform expression only in the presence of EGF [24
], suggesting the existence of important cross-talk between EGFRs and both SRs. Ligand-activated PRs and ERs are potent breast mitogens, and mammary epithelial cells that express PR also express ERα. Moreover, estrogen is usually required in order to induce the expression of PR. For these reasons, separating the effects of progesterone alone from estrogen have been difficult. Consequently, the direct role of PR isoforms in breast cancer remains poorly defined relative to the role of ERα in breast development and breast cancer.
PR and ER are expressed by a minority of non-dividing epithelial cells in the lumen of the mature mammary gland. PR- and ER-positive cells constitute only ~7-10% of the epithelial cell population in the normal adult mammary gland. This non-proliferative condition appears to be sustained by such inhibitory molecules as TGF-beta or high levels of p27, the CDK inhibitor (reviewed in [25
]). In response to communication between stromal and epithelial compartments, SR-positive epithelial cells express and secrete pro-proliferative molecules, such as Wnts or IGF-II, thereby inducing the proliferation of adjacent SR-negative epithelial cells [25
]. Recent data indicate that SR-positive cells in the breast may support the activity of nearby stem-like progenitor cells [27
]. In contrast to the normal breast, where proliferating cells are devoid of SRs, the majority of newly diagnosed breast cancers (~80%) express ER and PR. The existence of SR-positive proliferating cells in breast cancer implies that SR-positive cells undergo an early switch to autocrine stimulation and/or SR-positive lineages continue to divide. Breast cancer is not the only setting where PR-containing cells divide. In an in vivo
model of the mammary gland during pregnancy, PR-B colocalizes with cyclin D1 in BrdU-stained (dividing) cells [28
]. Thus, signaling pathways involved in normal mammary gland growth and development are likely reactivated during breast cancer progression.
Clinical findings indicate that PRs may play a direct role in breast cancer. Progesterone induces the estradiol-primed endometrium into a secretory phase, and thus progestins are routinely given with estrogen-hormone replacement therapy (HRT) in order to protect the uterus from the proliferative effects of unopposed estrogen action, thereby reducing the risk of uterine cancer. Progestins (via PR-A) are clearly inhibitory in the uterus, but play a proliferative role (via PR-B) in the developing breast [29
]. Progestin therapy increases breast cancer risk when administered with estrogen as part of combined HRT; tumors were larger and of higher grade relative to estrogen alone or placebo [1
]. Experimental data in mouse models of the postmenopausal breast indicate that progestins stimulate proliferation [30
]. While progestins are not carcinogens, progesterone might induce recently initiated pre-cancerous breast cell populations to inappropriately re-enter the cell cycle or stimulate dormant stem cells to undergo self-renewal. Additionally, synthetic progestins used in HRT (MPA; medroxyprogesterone acetate) interact with androgen receptors (AR), and may act as endocrine disruptors of AR signaling, which is protective in the normal breast [31
]. Indeed, AR is an important mediator of breast homeostatis, and may act primarily by induction of epithelial cell apoptosis or by direct inhibition of ER-alpha dependent signaling. It is thus critical to distinguish among the diverse actions of synthetic progestins (which interact with numerous SRs) relative to progesterone, the natural PR ligand.
Breast tumors develop resistance to endocrine-based treatments (anti-estrogens and/or aromatase inhibitors; androgens) as they progress. However, the majority (65%) of resistant breast cancers retain high levels of SRs (ERα, AR and PRs). In these resistant, SR-positive cancers, the rapid action of SRs at the membrane might begin to inappropriately trigger the classical transcriptional activities of SRs. In this way, PRs activated by extremely low or sub-threshold concentrations of hormone or PRs phosphorylated in the absence of hormone can activate membrane-associated signaling pathways, including c-Src kinase, EGFR, and the p42/p44 MAPK pathway. Elevation of MAPK activity and downstream signaling frequently occurs in breast cancer, providing a strong survival and proliferative stimulus to breast cancer cells. MAPK signaling downstream of EGFR or Her2 (erbB2) is also associated with resistance to endocrine therapies [32