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Differential Gene Regulation by the Two Progesterone Receptor Isoforms in Human Breast Cancer Cells*

  • Jennifer K. Richer
    Correspondence
    To whom correspondence should be addressed: Dept. of Medicine/Endocrinology, University of Colorado School of Medicine, Box B-151, 4200 East Ninth Ave., Denver, CO 80262. Tel.: 303-315-8443; Fax: 303-315-4525;
    Affiliations
    From the Department of Medicine/Endocrinology and the University of Colorado School of Medicine, Denver, Colorado 80262
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  • Britta M. Jacobsen
    Affiliations
    From the Department of Medicine/Endocrinology and the University of Colorado School of Medicine, Denver, Colorado 80262
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  • Nicole G. Manning
    Affiliations
    From the Department of Medicine/Endocrinology and the University of Colorado School of Medicine, Denver, Colorado 80262
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  • M. Greg Abel
    Affiliations
    From the Department of Medicine/Endocrinology and the University of Colorado School of Medicine, Denver, Colorado 80262
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  • Kathryn B. Horwitz
    Affiliations
    From the Department of Medicine/Endocrinology and the University of Colorado School of Medicine, Denver, Colorado 80262
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  • Douglas M. Wolf
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  • Author Footnotes
    * This work was supported by National Institutes of Health Grants DK48238 and CA26869, the National Foundation for Cancer Research (to K. B. H.), Department of Defense Breast Cancer Research Program Concept Award BC996535 (to J. K. R.), and an American Cancer Society IRG University of Colorado Cancer Center Seed Grant (to J. K. R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:November 20, 2001DOI:https://doi.org/10.1074/jbc.M110090200
      The PR-A and PR-B isoforms of progesterone receptors (PR) have different physiological functions, and their ratio varies widely in breast cancers. To determine whether the two PR regulate different genes, we used human breast cancer cell lines engineered to express one or the other isoform. Cells were treated with progesterone in triplicate, time-separated experiments, allowing statistical analyses of microarray gene expression data. Of 94 progesterone-regulated genes, 65 are uniquely regulated by PR-B, 4 uniquely by PR-A, and only 25 by both. Almost half the genes encode proteins that are membrane-bound or involved in membrane-initiated signaling. We also find an important set of progesterone-regulated genes involved in mammary gland development and/or implicated in breast cancer. This first, large scale study of PR gene regulation has important implications for the measurement of PR in breast cancers and for the many clinical uses of synthetic progestins. It suggests that it is important to distinguish between the two isoforms in breast cancers and that isoform-specific genes can be used to screen for ligands that selectively modulate the activity of PR-A or PR-B. Additionally, use of natural target genes, rather than “consensus” response elements, for transcription studies should improve our understanding of steroid hormone action.
      Progesterone receptors (PR)
      The abbreviations used are:
      PR
      progesterone receptor(s)
      HRT
      hormone replacement therapy
      ER
      estrogen receptor(s)
      ERR
      estrogen-related receptor
      MEM
      minimum essential medium
      RT
      reverse transcriptase
      PM
      perfectly matched
      MM
      mismatched
      GAPDH
      glyceraldehyde-3-phosphate dehydrogenase
      β2MG
      β2-microglobulin
      MCP
      monocyte chemotactic protein
      βHSD
      11β-hydroxysteroid dehydrogenase
      AF
      activation function
      1The abbreviations used are:PR
      progesterone receptor(s)
      HRT
      hormone replacement therapy
      ER
      estrogen receptor(s)
      ERR
      estrogen-related receptor
      MEM
      minimum essential medium
      RT
      reverse transcriptase
      PM
      perfectly matched
      MM
      mismatched
      GAPDH
      glyceraldehyde-3-phosphate dehydrogenase
      β2MG
      β2-microglobulin
      MCP
      monocyte chemotactic protein
      βHSD
      11β-hydroxysteroid dehydrogenase
      AF
      activation function
      are ligand-activated transcription factor members of the steroid hormone family of nuclear receptors. They exist naturally as two isoforms, PR-B and PR-A, transcribed from two promoters on a single gene (
      • Kastner P.
      • Krust A.
      • Turcotte B.
      • Stropp U.
      • Tora L.
      • Gronemeyer H.
      • Chambon P.
      ). Human PR-B are 933 amino acids in length and contain a unique activation function AF3 (
      • Sartorius C.A.
      • Melville M.Y.
      • Hovland A.R.
      • Tung L.
      • Takimoto G.S.
      • Horwitz K.B.
      ). PR-A lack the 164 N-terminal residues that contain AF3 and are 769 amino acids in length. Both isoforms are physiologically important. Mice lacking both PR display pleiotropic reproductive abnormalities, incomplete mammary gland development, and impaired thymic function and sexual behavior (
      • Lydon J.P.
      • DeMayo F.J.
      • Funk C.R.
      • Mani S.K.
      • Hughes A.R.
      • Montgomery C.A., Jr.
      • Shyamala G.
      • Conneely O.M.
      • O'Malley B.W.
      ), whereas those lacking only PR-A exhibit a subset of these phenotypes (
      • Mulac-Jericevic B.
      • Mullinax R.A.
      • DeMayo F.J.
      • Lydon J.P.
      • Conneely O.M.
      ).
      Clinically, PR are important therapeutic targets. Progestational agents are widely used for oral contraception, menopausal hormone replacement therapy (HRT), and to treat breast cancer and endometrial hyperplasia (
      • Kimmick G.G.
      • Muss H.B.
      ,
      • Howell A.
      • Anderson E.
      • Blamey R.
      • Clarke R.B.
      • Dixon J.M.
      • Dowsett M.
      • Johnston S.R.
      • Miller W.R.
      • Nicholson R.
      • Robertson J.F.
      ). Antiprogestins are in clinical trials for contraception, induction of labor, and the treatment of meningiomas, endometriosis, and endometrial cancers. In breast cancers, total PR levels are routinely measured as a guide to hormone therapy and as markers of disease prognosis (
      • Horwitz K.B.
      • Wei L.L.
      • Sedlacek S.M.
      • d'Arville C.N.
      ,
      • Horwitz K.B.
      • McGuire W.L.
      ,
      • Horwitz K.B.
      • McGuire W.L.
      • Pearson O.H.
      • Segaloff A.
      ,
      • McGuire W.L.
      ). Interestingly, whereas progestins added to HRT successfully decrease the incidence of endometrial cancer, they increase the incidence of breast cancer (
      • Schairer C.
      • Lubin J.
      • Troisi R.
      • Sturgeon S.
      • Brinton L.
      • Hoover R.
      ,
      • Persson I.
      • Weiderpass E.
      • Bergkvist L.
      • Bergstrom R.
      • Schairer C.
      ).
      Little is known regarding the unique roles of the two PR isoforms in progesterone target tissues. In vitro, the two receptors have markedly different transcriptional effects on progestin-responsive promoters (
      • Sartorius C.A.
      • Melville M.Y.
      • Hovland A.R.
      • Tung L.
      • Takimoto G.S.
      • Horwitz K.B.
      ,
      • Meyer M.-E.
      • Quirin-Stricker C.
      • Lerouge T.
      • Bocquel M.-T.
      • Gronemeyer H.
      ,
      • Vegeto E.
      • Shabaz M.M.
      • Wen D.X.
      • Goldman M.E.
      • O'Malley B.W.
      • McDonnell D.P.
      ,
      • Tung L.
      • Mohamed M.K.
      • Hoeffler J.P.
      • Takimoto G.S.
      • Horwitz K.B.
      ,
      • Sartorius C.A.
      • Tung L.
      • Takimoto G.S.
      • Horwitz K.B.
      ). The antiprogestin RU486 has partial agonist effects only on PR-B, whereas only PR-A inhibit PR-B and other steroid receptors including estrogen receptors (ER) (
      • McDonnell D.P.
      • Shahbaz M.M.
      • Vegeto E.
      • Goldman M.E.
      ,
      • Hovland A.R.
      • Powell R.L.
      • Takimoto G.S.
      • Tung L.
      • Horwitz K.B.
      ,
      • Takimoto G.S.
      • Tasset D.M.
      • Eppert A.C.
      • Horwitz K.B.
      ). In vivo, the two PR isoforms are usually coexpressed in normal cells, yet their ratio varies dramatically in different tissues, physiological states, and in disease (
      • Boyd-Leinen P.A.
      • Fournier D.
      • Spelsberg T.C.
      ,
      • Spelsberg T.C.
      • Halberg F.
      ,
      • Kato J.
      • Hirata S.
      • Nozawa A.
      • Mouri N.
      ). For example, in the estrogen-treated primate, the hypothalamus expresses an excess of PR-B, but the pituitary expresses an excess of PR-A (
      • Baez M.
      • Sargan D.R.
      • Elbrecht A.
      • Kulomaa M.S.
      • Zarucki S.T.
      • Tsai M.J.
      • O'Malley B.W.
      ,
      • Bethea C.L.
      • Widmann A.A.
      ). In human endometrium the levels and ratio of PR-A to PR-B vary extensively during the menstrual cycle (
      • Mote P.A.
      • Balleine R.L.
      • McGowan E.M.
      • Clarke C.L.
      ,
      • Mote P.A.
      • Balleine R.L.
      • McGowan E.M.
      • Clarke C.L.
      ,
      • Mangal R.K.
      • Wiehle R.D.
      • Poindexter III, A.N.
      • Weigel N.L.
      ,
      • Feil P.D.
      • Clarke C.L.
      • Satyaswaroop P.G.
      ), and overexpression of PR-B is associated with highly malignant forms of endometrial, cervical, and ovarian cancers (
      • Farr C.J.
      • Easty D.J.
      • Ragoussis J.
      • Collignon J.
      • Lovell-Badge R.
      • Goodfellow P.N.
      ,
      • Fujimoto J.
      • Ichigo S.
      • Hirose R.
      • Sakaguchi H.
      • Tamaya T.
      ).
      With regard to the mammary gland, in transgenic mice, 3:1 overexpression of PR-A over PR-B results in extensive epithelial cell hyperplasia, excessive ductal branching, and a disorganized basement membrane, all features associated with neoplasia (
      • Shyamala G.
      • Yang X.
      • Silberstein G.
      • Barcellos-Hoff M.H.
      • Dale E.
      ). In contrast, overexpression of PR-B leads to premature ductal growth arrest and inadequate lobulo-alveolar differentiation (
      • Shyamala G.
      • Yang X.
      • Cardiff R.D.
      • Dale E.
      ). Interestingly, PR-A null mice, which express only PR-B, exhibit normal mammary gland development, yet the same mice display severe uterine hyperplasia and reproductive defects (
      • Mulac-Jericevic B.
      • Mullinax R.A.
      • DeMayo F.J.
      • Lydon J.P.
      • Conneely O.M.
      ). Collectively, these data suggest that PR-A and PR-B have physiologically different functions in different tissues and that alterations in their ratios carry different consequences depending on the tissue.
      Although PR levels are routinely measured in breast cancers for clinical decision making, only two studies have examined the levels of the two isoforms. An analysis of 202 PR-positive breast cancers by immunoblotting shows that expression levels of PR-A are higher than PR-B in 59% of tumors and are 4-fold or greater in 25% of tumors (
      • Graham J.D.
      • Yeates C.
      • Balleine R.L.
      • Harvey S.S.
      • Milliken J.S.
      • Bilous A.M.
      • Clarke C.L.
      ). In another study of 32 PR-positive breast cancers, excess PR-B correlated with the absence of Her-2/neu indicating a good prognosis, whereas excess PR-A correlated with a poorly differentiated phenotype and higher tumor grade (
      • Bamberger A.M.
      • Milde-Langosch K.
      • Schulte H.M.
      • Loning T.
      ). Overexpression of PR-A in cultured human breast cancer cells results in marked morphological changes and loss of adherent properties (
      • McGowan E.M.
      • Clarke C.L.
      ), suggesting, as do the transgenic mice data, that an excess of PR-A is particularly harmful in the breast.
      Little is known at present about the molecular mechanisms that might explain these differences. We therefore undertook the first systematic, large scale comparison of gene regulation by the two PR, using a unique human breast cancer cell model for this purpose. Wild-type T47Dco breast cancer cells express equimolar levels of PR-A and PR-B in an estrogen-independent manner (
      • Horwitz K.B.
      • Mockus M.B.
      • Lessey B.A.
      ). To study differential gene regulation by the two PR isoforms independently, we isolated a PR-negative subline of T47Dco (designated T47D-Y cells) and then engineered the T47D-Y to stably express equivalent levels of either PR-B (T47D-YB cells) or PR-A (T47D-YA cells) (
      • Sartorius C.A.
      • Groshong S.D.
      • Miller L.A.
      • Powell R.L.
      • Tung L.
      • Takimoto G.S.
      • Horwitz K.B.
      ). Because these are pure cell populations, and all of the cells have the same parental-cell background, the PR isoform-specific effects of progesterone on gene transcription can be quantitatively and reproducibly investigated in a tightly controlled manner.
      Our data, based on triplicate determinations, demonstrate that in response to progesterone, PR-A and PR-B primarily regulate different subsets of genes, and although PR-B are transcriptionally more active, there are genes that are uniquely regulated by PR-A. These subsets include genes known to be involved in breast cancer and/or mammary gland development but not previously known to be progesterone targets. Progesterone regulation of many of these genes would be deleterious in breast cancers. A surprisingly large number of genes are targeted to the cell membrane or involved in membrane-initiated signaling. Other gene clusters are involved in metabolism, transcription, cell growth and apoptosis, and nucleic acid and protein processing. The results suggest that PR-A and PR-B have different molecular functions and that it may be important to quantify either the PR isoform content of breast cancers or their gene targets, rather than total PR.

      Acknowledgments

      We acknowledge the assistance of the University of Colorado Center Cancer Center Gene Expression and Biostatistics Core Laboratories and the University of Colorado Health Science Center for Computational Pharmacology. The University of Colorado has submitted a patent describing the commercial applications of these genes.

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