Epithelial-Stromal Interaction and Progesterone Receptors in the Mouse Uterus

ABSTRACT

Healthy uterine function depends on the balanced interaction of the ovarian steroids estrogen and progesterone (P4) signaling through their respective receptors. The expression of each receptor is regulated by the other through crucial cross talk between the epithelial and stromal compartments. Ablation of the progesterone receptor (PR) results in complete infertility in mice, and evidence increasingly demonstrates that the PR is a major mediator of epithelial-stromal cross talk and events leading to the disruption of this communication can lead to P4 resistance in the uterus. This resistance, through impaired P4 signaling, can be at the level of the PR itself, coregulators, and downstream effectors. The mechanisms underlying P4 resistance is of critical importance in women's health because this defect is seen in a wide variety of diseases including infertility, endometriosis, endometrial carcinoma, polycystic ovarian syndrome, and leiomyomas. By using mouse models of PR signaling, many of these mechanisms are beginning to be elucidated and aid in the development of effective therapies for treatment of uterine diseases.

KEYWORDS

Progesterone receptor - progesterone resistance - uterus

REFERENCES

• 1 DeMayo F J, Zhao B, Takamoto N, Tsai S Y. Mechanisms of action of estrogen and progesterone.  Ann N Y Acad Sci. 2002;  955 48-59
• 2 Huet-Hudson Y M, Andrews G K, Dey S K. Cell type-specific localization of c-myc protein in the mouse uterus: modulation by steroid hormones and analysis of the periimplantation period.  Endocrinology. 1989;  125(3) 1683-1690
• 3 Carson D D, Bagchi I, Dey S K et al.. Embryo implantation.  Dev Biol. 2000;  223(2) 217-237
• 4 Giudice L C, Kao L C. Endometriosis.  Lancet. 2004;  364(9447) 1789-1799
• 5 Bulun S E. Endometriosis.  N Engl J Med. 2009;  360(3) 268-279
• 6 Ito K, Utsunomiya H, Yaegashi N, Sasano H. Biological roles of estrogen and progesterone in human endometrial carcinoma—new developments in potential endocrine therapy for endometrial cancer.  Endocr J. 2007;  54(5) 667-679
• 7 Pijnenborg J M, Romano A, Dam-de Veen G C et al.. Aberrations in the progesterone receptor gene and the risk of recurrent endometrial carcinoma.  J Pathol. 2005;  205(5) 597-605
• 8 Junqueira M G, da Silva I D, Nogueira-de-Souza N C et al.. Progesterone receptor (PROGINS) polymorphism and the risk of endometrial cancer development.  Int J Gynecol Cancer. 2007;  17(1) 229-232
• 9 Rein M S, Barbieri R L, Friedman A J. Progesterone: a critical role in the pathogenesis of uterine myomas.  Am J Obstet Gynecol. 1995;  172(1 Pt 1) 14-18
• 10 Parker W H. Etiology, symptomatology, and diagnosis of uterine myomas.  Fertil Steril. 2007;  87(4) 725-736
• 11 Flake G P, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review.  Environ Health Perspect. 2003;  111(8) 1037-1054
• 12 Giudice L C. Endometrium in PCOS: implantation and predisposition to endocrine CA.  Best Pract Res Clin Endocrinol Metab. 2006;  20(2) 235-244
• 13 Story L, Kennedy S. Animal studies in endometriosis: a review.  ILAR J. 2004;  45(2) 132-138
• 14 Wang C, Mavrogianis P A, Fazleabas A T. Endometriosis is associated with progesterone resistance in the baboon (Papio anubis) oviduct: evidence based on the localization of oviductal glycoprotein 1 (OVGP1).  Biol Reprod. 2009;  80(2) 272-278
• 15 Balleine R L, Earls P J, Webster L R et al.. Expression of progesterone receptor A and B isoforms in low-grade endometrial stromal sarcoma.  Int J Gynecol Pathol. 2004;  23(2) 138-144
• 16 Burney R O, Talbi S, Hamilton A E et al.. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.  Endocrinology. 2007;  148(8) 3814-3826
• 17 van Kaam K J, Romano A, Schouten J P, Dunselman G A, Groothuis P G. Progesterone receptor polymorphism + 331G/A is associated with a decreased risk of deep infiltrating endometriosis.  Hum Reprod. 2007;  22(1) 129-135
• 18 Arnett-Mansfield R L, deFazio A, Wain G V et al.. Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium.  Cancer Res. 2001;  61(11) 4576-4582
• 19 Tsai M J, O'Malley B W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.  Annu Rev Biochem. 1994;  63 451-486
• 20 Ribeiro R C, Kushner P J, Baxter J D. The nuclear hormone receptor gene superfamily.  Annu Rev Med. 1995;  46 443-453
• 21 Conneely O M, Maxwell B L, Toft D O, Schrader W T, O'Malley B W. The A and B forms of the chicken progesterone receptor arise by alternate initiation of translation of a unique mRNA.  Biochem Biophys Res Commun. 1987;  149(2) 493-501
• 22 Li X, O'Malley B W. Unfolding the action of progesterone receptors.  J Biol Chem. 2003;  278(41) 39261-39264
• 23 Tranguch S, Wang H, Daikoku T, Xie H, Smith D F, Dey S K. FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific.  J Clin Invest. 2007;  117(7) 1824-1834
• 24 Owen G I, Richer J K, Tung L, Takimoto G, Horwitz K B. Progesterone regulates transcription of the p21(WAF1) cyclin-dependent kinase inhibitor gene through Sp1 and CBP/p300.  J Biol Chem. 1998;  273(17) 10696-10701
• 25 Gao J, Mazella J, Seppala M, Tseng L. Ligand activated hPR modulates the glycodelin promoter activity through the Sp1 sites in human endometrial adenocarcinoma cells.  Mol Cell Endocrinol. 2001;  176(1-2) 97-102
• 26 Gizard F, Robillard R, Gervois P et al.. Progesterone inhibits human breast cancer cell growth through transcriptional upregulation of the cyclin-dependent kinase inhibitor p27Kip1 gene.  FEBS Lett. 2005;  579(25) 5535-5541
• 27 Boonyaratanakornkit V, Bi Y, Rudd M, Edwards D P. The role and mechanism of progesterone receptor activation of extra-nuclear signaling pathways in regulating gene transcription and cell cycle progression.  Steroids. 2008;  73(9-10) 922-928
• 28 Lydon J P, DeMayo F J, Funk C R et al.. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.  Genes Dev. 1995;  9(18) 2266-2278
• 29 Lee K, Jeong J, Tsai M J et al.. Molecular mechanisms involved in progesterone receptor regulation of uterine function.  J Steroid Biochem Mol Biol. 2006;  102(1) 41-50
• 30 Fang Z, Yang S, Lydon J P et al.. Intact progesterone receptors are essential to counteract the proliferative effect of estradiol in a genetically engineered mouse model of endometriosis.  Fertil Steril. 2004;  82(3) 673-678
• 31 Mulac-Jericevic B, Mullinax R A, DeMayo F J, Lydon J P, Conneely O M. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform.  Science. 2000;  289(5485) 1751-1754
• 32 Mulac-Jericevic B, Lydon J P, DeMayo F J, Conneely O M. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform.  Proc Natl Acad Sci U S A. 2003;  100(17) 9744-9749
• 33 Kim J J, Buzzio O L, Li S, Lu Z. Role of FOXO1A in the regulation of insulin-like growth factor-binding protein-1 in human endometrial cells: interaction with progesterone receptor.  Biol Reprod. 2005;  73(4) 833-839
• 34 Takano M, Lu Z, Goto T et al.. Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells.  Mol Endocrinol. 2007;  21(10) 2334-2349
• 35 Bulun S E, Cheng Y H, Yin P et al.. Progesterone resistance in endometriosis: link to failure to metabolize estradiol.  Mol Cell Endocrinol. 2006;  248(1-2) 94-103
• 36 Attia G R, Zeitoun K, Edwards D, Johns A, Carr B R, Bulun S E. Progesterone receptor isoform A but not B is expressed in endometriosis.  J Clin Endocrinol Metab. 2000;  85(8) 2897-2902
• 37 Aghajanova L, Hamilton A, Kwintkiewicz J, Vo K C, Giudice L C. Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis.  Biol Reprod. 2009;  80(1) 105-114
• 38 Xu J, Li Q. Review of the in vivo functions of the p160 steroid receptor coactivator family.  Mol Endocrinol. 2003;  17(9) 1681-1692
• 39 McKenna N J, O'Malley B W. Minireview: nuclear receptor coactivators—an update.  Endocrinology. 2002;  143(7) 2461-2465
• 40 Shibata H, Spencer T E, Onate S A et al.. Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action.  Recent Prog Horm Res. 1997;  52 141-164
• 41 Hofman K, Swinnen J V, Verhoeven G, Heyns W. Coactivation of an endogenous progesterone receptor by TIF2 in COS-7 cells.  Biochem Biophys Res Commun. 2002;  295(2) 469-474
• 42 Jeong J W, Lee K Y, Han S J et al.. The p160 steroid receptor coactivator 2, SRC-2, regulates murine endometrial function and regulates progesterone-independent and -dependent gene expression.  Endocrinology. 2007;  148(9) 4238-4250
• 43 Xu J, Qiu Y, DeMayo F J, Tsai S Y, Tsai M J, O'Malley B W. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene.  Science. 1998;  279(5358) 1922-1925
• 44 Gehin M, Mark M, Dennefeld C, Dierich A, Gronemeyer H, Chambon P. The function of TIF2/GRIP1 in mouse reproduction is distinct from those of SRC-1 and p/CIP.  Mol Cell Biol. 2002;  22(16) 5923-5937
• 45 Soyal S M, Mukherjee A, Lee K Y et al.. Cre-mediated recombination in cell lineages that express the progesterone receptor.  Genesis. 2005;  41(2) 58-66
• 46 Mukherjee A, Soyal S M, Fernandez-Valdivia R et al.. Steroid receptor coactivator 2 is critical for progesterone-dependent uterine function and mammary morphogenesis in the mouse.  Mol Cell Biol. 2006;  26(17) 6571-6583
• 47 Xu J, Liao L, Ning G, Yoshida-Komiya H, Deng C, O'Malley B W. The steroid receptor coactivator SRC-3 (p/CIP/RAC3/AIB1/ACTR/TRAM-1) is required for normal growth, puberty, female reproductive function, and mammary gland development.  Proc Natl Acad Sci U S A. 2000;  97(12) 6379-6384
• 48 Gregory C W, Wilson E M, Apparao K B et al.. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium.  J Clin Endocrinol Metab. 2002;  87(6) 2960-2966
• 49 Mukherjee A, Amato P, Allred D C, DeMayo F J, Lydon J P. Steroid receptor coactivator 2 is required for female fertility and mammary morphogenesis: insights from the mouse, relevance to the human.  Nucl Recept Signal. 2007;  5 11
• 50 Sakaguchi H, Fujimoto J, Sun W S, Tamaya T. Clinical implications of steroid receptor coactivator (SRC)-3 in uterine endometrial cancers.  J Steroid Biochem Mol Biol. 2007;  104(3-5) 237-240
• 51 Lonard D M, O'Malley B W. Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation.  Mol Cell. 2007;  27(5) 691-700
• 52 Tranguch S, Cheung-Flynn J, Daikoku T et al.. Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation.  Proc Natl Acad Sci U S A. 2005;  102(40) 14326-14331
• 53 Daikoku T, Tranguch S, Friedman D B, Das S K, Smith D F, Dey S K. Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus.  Mol Endocrinol. 2005;  19(3) 683-697
• 54 Hirota Y, Tranguch S, Daikoku T et al.. Deficiency of immunophilin FKBP52 promotes endometriosis.  Am J Pathol. 2008;  173(6) 1747-1757
• 55 Cunha G R, Cooke P S, Kurita T. Role of stromal-epithelial interactions in hormonal responses.  Arch Histol Cytol. 2004;  67(5) 417-434
• 56 Kurita T, Lee K J, Cooke P S, Lydon J P, Cunha G R. Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus.  Biol Reprod. 2000;  62(4) 831-838
• 57 Kurita T, Lee K J, Cooke P S, Taylor J A, Lubahn D B, Cunha G R. Paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract.  Biol Reprod. 2000;  62(4) 821-830
• 58 Zeitoun K, Takayama K, Sasano H et al.. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.  J Clin Endocrinol Metab. 1998;  83(12) 4474-4480
• 59 Dassen H, Punyadeera C, Kamps R et al.. Estrogen metabolizing enzymes in endometrium and endometriosis.  Hum Reprod. 2007;  22(12) 3148-3158
• 60 Yang S, Fang Z, Gurates B et al.. Stromal PRs mediate induction of 17beta-hydroxysteroid dehydrogenase type 2 expression in human endometrial epithelium: a paracrine mechanism for inactivation of E2.  Mol Endocrinol. 2001;  15(12) 2093-2105
• 61 Cheng Y H, Imir A, Suzuki T et al.. SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium.  Biol Reprod. 2006;  75(4) 605-614
• 62 Cheng Y H, Imir A, Fenkci V, Yilmaz M B, Bulun S E. Stromal cells of endometriosis fail to produce paracrine factors that induce epithelial 17beta-hydroxysteroid dehydrogenase type 2 gene and its transcriptional regulator Sp1: a mechanism for defective estradiol metabolism.  Am J Obstet Gynecol. 2007;  196(4) 391-397
• 63 Takamoto N, Zhao B, Tsai S Y, DeMayo F J. Identification of Indian hedgehog as a progesterone-responsive gene in the murine uterus.  Mol Endocrinol. 2002;  16(10) 2338-2348
• 64 Matsumoto H, Zhao X, Das S K, Hogan B L, Dey S K. Indian hedgehog as a progesterone-responsive factor mediating epithelial-mesenchymal interactions in the mouse uterus.  Dev Biol. 2002;  245(2) 280-290
• 65 Dyer M A, Farrington S M, Mohn D, Munday J R, Baron M H. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo.  Development. 2001;  128(10) 1717-1730
• 66 St-Jacques B, Hammerschmidt M, McMahon A P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation.  Genes Dev. 1999;  13(16) 2072-2086
• 67 Lee K, Jeong J, Kwak I et al.. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus.  Nat Genet. 2006;  38(10) 1204-1209
• 68 Wang L H, Tsai S Y, Cook R G, Beattie W G, Tsai M J, O'Malley B W. COUP transcription factor is a member of the steroid receptor superfamily.  Nature. 1989;  340(6229) 163-166
• 69 Ritchie H H, Wang L H, Tsai S, O'Malley B W, Tsai M J. COUP-TF gene: a structure unique for the steroid/thyroid receptor superfamily.  Nucleic Acids Res. 1990;  18(23) 6857-6862
• 70 Wang L H, Ing N H, Tsai S Y, O'Malley B W, Tsai M J. The COUP-TFs compose a family of functionally related transcription factors.  Gene Expr. 1991;  1(3) 207-216
• 71 Pereira F A, Tsai M J, Tsai S Y. COUP-TF orphan nuclear receptors in development and differentiation.  Cell Mol Life Sci. 2000;  57(10) 1388-1398
• 72 Pereira F A, Qiu Y, Zhou G, Tsai M J, Tsai S Y. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development.  Genes Dev. 1999;  13(8) 1037-1049
• 73 Takamoto N, Kurihara I, Lee K, Demayo F J, Tsai M J, Tsai S Y. Haploinsufficiency of chicken ovalbumin upstream promoter transcription factor II in female reproduction.  Mol Endocrinol. 2005;  19(9) 2299-2308
• 74 Kurihara I, Lee D K, Petit F G et al.. COUP-TFII mediates progesterone regulation of uterine implantation by controlling ER activity.  PLoS Genet. 2007;  3(6) e102
• 75 Paria B C, Ma W, Tan J et al.. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors.  Proc Natl Acad Sci U S A. 2001;  98(3) 1047-1052
• 76 Ying Y, Zhao G Q. Detection of multiple bone morphogenetic protein messenger ribonucleic acids and their signal transducer, Smad1, during mouse decidualization.  Biol Reprod. 2000;  63(6) 1781-1786
• 77 Lee K Y, Jeong J W, Wang J R et al.. Bmp2 is critical for the murine uterine decidual response.  Mol Cell Biol. 2007;  27(15) 5468-5478
• 78 Li Q X, Kannan A, Wang W et al.. Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human.  J Biol Chem. 2007;  282(43) 31725-31732
• 79 Zeitoun K, Takayama K, Michael M D, Bulun S E. Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element.  Mol Endocrinol. 1999;  13(2) 239-253
• 80 Bulun S E, Zeitoun K M, Takayama K, Simpson E, Sasano H. Aromatase as a therapeutic target in endometriosis.  Trends Endocrinol Metab. 2000;  11(1) 22-27