The Effect of Progestins on Prolactin Receptor Gene Transcription in Human Breast Cancer Cells

(iii) inducible PR-B cells (Y iB), (iv) stable PR-B plus inducible PR-A cells (B iA), and (v) stable PR-A plus inducible PR-B cells (A iB). Expression levels of each isoform and/or the PR-A/PR-B ratios could be tightly controlled by the dose of induceras demonstrated by immunoblotting and transcription studies. Induced PRs underwent normal progestin-dependent phosphorylation and down-regulation and regulated exogenous promoters as well as endogenous gene expression. Transcription of exogenous promoters was dependent on the PR-A/PR-B ratio, whereas transcription of endogenous genes was more complex. Finally, we have described several genes that are regulated by induced PR-A even in the absence of ligand.

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“…PRLRs are known to be progesterone-regulated (44). Their expression is complex and involves multiple tissue specific promoters.…”

Section: Discussionmentioning

confidence: 99%

New Human Breast Cancer Cells to Study Progesterone Receptor Isoform Ratio Effects and Ligand-independent Gene Regulation

Jacobsen

Richer

Schittone

et al. 2002

Journal of Biological Chemistry

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“…It is believed that estrogen can a ect mammary gland development growth by virtue of its ability to induce progesterone receptors (Haslam, 1988;Wang et al, 1990) and PRL receptors (Ormandy et al, 1992). The addition of progesterone and PRL resulted in extensive penetration of the mammary fat pad, along with dichotomous and subordinate branching as would be expected during normal pubertal development.…”

Section: Discussionmentioning

confidence: 99%

Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth

et al. 2000

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Prolactin (PRL), interacting with other hormones from the pituitary, gonad, and placenta, activates speci®c signals that drive the appropriately timed morphological and functional development of the mammary gland. A mouse model of isolated PRL de®ciency (PRL 7/7 ) was created by gene disruption in an e ort to further understand the molecular basis of mammary gland development and breast cancer. Whereas primary ductal growth was normal in PRL 7/7 mice, ductal arborization was minimal (branches/mm 2 =1.5+0.5), and lobular budding was absent. Replacement therapy with PRL injections stimulated a modest degree of lobular budding and ductal arborization (3.75+0.9). Pituitary transplants to the kidney capsule of PRL 7/7 mice restored lobular budding and ductal arborization, to the full extent of that seen in control animals (20.3+5.5). Pregnancy, established by mating progesterone-treated PRL 7/7 females with PRL 7/7 males, led to complete morphological development of the mammary gland, appropriate to the gestational stage. PRL treatment stimulated tyrosine phosphorylation and DNA binding activity of Stat5a, but not Stat1 in PRL 7/7 or PRL +/7 females, and Stat5a, but not Stat1, was elevated by estradiol within 24 h. PRL-de®cient mice were crossed with mice expressing a dominant oncogene (polyoma middle-T antigen driven by the MMTV promoter, PyVT mice). Palpable (1 mm 3 ) tumors were detected an average of 9 days earlier in hormonally normal females (PRL +/7 :PyVT) compared with littermates that were PRL-de®cient (PRL 7/7 :PyVT). The growth rate of PyVT-induced tumors was 30% faster in PRL +/7 , than in PRL 7/7 females.

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“…Plasmids bearing the progestin-responsive mouse mammary tumor virus long terminal repeat linked to chloramphenicol acetyltransferase (pMSG-CAT) and bacterial ␤-galactosidase sequences (pCH110) were obtained from Pharmacia LKB Biotechnology (North Ryde, Sydney, Australia); pSG5-hPR1, pAER encoding human ER, PR(ϩ464,ϩ1105), and PR(Ϫ711,ϩ31) in minimal pBLCAT vectors were gifts from Dr. Pierre Chambon, Strasbourg, France; and fatty acid synthetase cDNA was a gift from Dr. Henri Rochefort, Montpellier, France. The prolactin receptor (PRLR) cDNA and effects of progestins on PRLR have been described previously (37). Human fibroblast ␤-actin (38), ␣-tubulin (b␣1) (39), and 36B4 (40) cDNAs have been described previously.…”

Section: Methodsmentioning

confidence: 99%

“…Rate-Nuclear run-on transcription assays included both positive (tubulin) and negative (pUC) controls as well as a control gene (prolactin receptor, PRLR) whose regulation by estrogen and progestins was known to be different from PR; PRLR expression is stimulated by progestins but unaffected by estrogen in T-47D cells (37). Initial experiments focussed on a detailed analysis of the time course of PR transcription rate inhibition by the synthetic progestin ORG 2058.…”

Section: Progestin and Estrogen Modulation Of Pr Transcriptionmentioning

confidence: 99%

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

Graham

Roman

McGowan

et al. 1995

Journal of Biological Chemistry

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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...

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The Effect of Progestins on Prolactin Receptor Gene Transcription in Human Breast Cancer Cells

Cited by 22 publications

References 23 publications

New Human Breast Cancer Cells to Study Progesterone Receptor Isoform Ratio Effects and Ligand-independent Gene Regulation

New Human Breast Cancer Cells to Study Progesterone Receptor Isoform Ratio Effects and Ligand-independent Gene Regulation

Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth

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

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