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Sylvia C. Hewitt, The Five W’s of Progesterone Receptors A and B: Now We Know Where and When, Endocrinology, Volume 147, Issue 12, 1 December 2006, Pages 5501–5502, https://doi.org/10.1210/en.2006-1314
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The endometrium and mammary glands are both complex tissues comprised of multiple cell types. The endometrium consists of stromal cells that support epithelial cells lining the uterine lumen as well as glandular epithelial structures that emanate from the lumen (1). The mammary gland consists of stromal adipose cells in which branched epithelial ducts develop (2). Both of these tissues are exquisitely sensitive to ovarian steroid hormones first at puberty, during which progesterone and estrogen orchestrate the intricate maturation of the tissues, and then in the adult female during ovarian cycles, throughout establishment and maintenance of pregnancy, and during initiation and sustenance of lactation. The stromal cells in both tissues are thought to secrete paracrine signals that communicate to the epithelial cells (3).
The responses to progesterone and estrogen are initiated by their respective nuclear receptors. In the case of the progesterone receptors (PR), two forms of the PR protein, PRA and PRB, have been identified in tissues and are encoded by the same gene but differ by an extended N-terminal region in PRB (4). In vitro studies have shown that PRA and PRB homodimers and heterodimers each have distinct transcriptional regulatory activities, including PRB-mediated inhibition of PRA and estrogen receptor transcriptional activities (5). The PR isoforms have also been studied in tissues and have been shown to be present in varying ratios by Western blotting, which can distinguish the two by virtue of their different molecular weights. Ablation of both PRs or selective deletion of PRA or PRB has indicated distinct biological roles of the receptors in mouse tissues (4). The full PR knockout (KO) lacks the uterine responses of decidualization and opposition of estrogen-induced hyperplasia. Additionally, the PRKO lacks full mammary epithelial development during pregnancy. The uterine phenotypes are rescued in the PRBKO, which expresses only PRA, indicating that PRA is critical for these uterine responses; whereas the PRAKO recovers the mammary gland development, illustrating the importance of PRB for pregnancy-associated mammary growth. Mouse models in which the mammary tissue selectively overexpresses PRA or PRB transgenes have suggested the importance of maintaining a balance between the isoforms, because the PRB-overexpressing gland lacks ductal elongation, and the PRA-overexpressing gland has ductal hyperplasia and disruption of the basement membrane (6, 7).
