Preferential Stimulation of Human Progesterone Receptor B Expression by Estrogen in T-47D Human Breast Cancer Cells

Abstract

Human progesterone receptor (PR) expression is controlled by two promoter regions giving rise to transcripts encoding PR A and B proteins. It is unknown whether estrogen and progesterone, the major physiological modulators of PR expression, exert their effects equally on the PR promoters. The aim of this study was to analyze estrogen and progestin effects on PR promoters, PR-encoding transcripts, and PR A and B proteins in T-47D human breast cancer cells. The progestin ORG 2058 caused a prolonged decrease in transcription of the PR gene and also abrogated estrogen stimulation of PR transcription. Estradiol (E2) treatment increased the activity of the B but not the A promoter transfected into T-47D cells. ORG 2058 had no effect on the basal or E2-stimulated activity of either promoter. E2 caused a preferential increase in transcripts derived from promoter B, whereas progestins decreased the levels of all PR transcripts. E2 preferentially increased the concentration of the PR B protein and caused a decrease in the PR A/B ratio. This demonstration that estrogen and progestin independently control the synthesis of transcripts arising from the PR promoters and that estrogen alters the cellular PR A/B ratio provides possible mechanisms underlying the cell and tissue specificity of PR regulation.Progesterone plays a major role in mammalian reproductive biology, including development of the normal mammary gland and expression of its differentiated function during pregnancy, and promotion of uterine differentiation and preparation for implantation in pregnancy (1). Progesterone effects are mediated via the nuclear progesterone receptor (PR) 1 and control of progesterone action is achieved largely although not exclusively by control of the concentration of PR. The major physiological modulators of PR concentration are the ovarian hormone 17␤-estradiol (E2), and progesterone itself, which binds to PR in order to exert progestational effects but also participates in regulation of its own receptor.Understanding of PR regulation derives largely from detailed and elegant studies in the mammalian uterus and in breast cancer cells, which led to the generally accepted view that estrogen increases and progestins decrease PR expression (2, 3). However, the advent of monoclonal antibodies to the steroid hormone receptors and the examination of PR expression at an individual cell level have shown that PR regulation may be more complex than previously suspected. Regulation of PR in the uterus is a cell-specific event, and PR regulation in the normal breast in vivo may be different from its regulation in the uterus and in breast cancer cells. In the endometrium, immunohistochemical evidence supports the view that the cyclical effects of estrogen and progesterone are mediated by estrogen stimulation of PR and progesterone down-regulation of both PR and estrogen receptor (ER) (4 -7). However, progesterone down-regulation of PR is not a uniform effect in the uterus, as myometrial and stromal PR levels are not decreased by progesterone and...

Progesterone Receptor A and B Isoforms in the Human Breast and Its Disorders

“…Our results also demonstrated that PRA was always equally expressed with PRB in benign proliferative lesions but sometimes dominantly expressed in IDC. These results are consistent with findings of PR isoforms in human breast tumors examined using immunoblot analysis by Graham et al 4) However, Akahira et al 27) recently demonstrated that PRB was dominantly expressed in all types or groups of epithelial ovarian carcinoma, another estrogendependent human neoplasm, using both immunohistochemistry and RT-PCR. The biological significance and/ or possible significance of PR isoforms in human estrogen-dependent neoplasms requires further investigation for clarification.…”

“…4) However, immunolocalization of PR isoform proteins has not been reported in detail in human breast cancer. Therefore, in this study, we first immunolocalized PRA and PRB in human breast cancer and intraductal epithelial proliferative lesions.…”

Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP

“…Furthermore, because PRB is more transcriptionally active than PRA, tumors with a high PRA:PRB are more hormone refractive. PRB is often a stronger activator of target genes such as cyclin D1 that is overexpressed in many breast cancers (Graham et al, 1995). The role of these isoforms is indeed complex (Kariagina et al, 2008).…”

Protein kinases mediate ligand-independent derepression of sumoylated progesterone receptors in breast cancer cells

“…In contrast to the normal breast where PR-A and PR-B are coexpressed at equal levels, breast cancers often contain aberrant PR-A:PR-B ratios, an early event in breast carcinogenesis (29). As tumors progress, frequent high A:B ratios are most often associated with loss of PR-B protein (rather than gain of PR-A) (30). In fact, PR loss is an excellent marker of heightened protein tyrosine kinase activities and tamoxifen resistance (31).…”