Breast Cancer Research and Treatment

, Volume 126, Issue 3, pp 621–636 | Cite as

Classical membrane progesterone receptors in murine mammary carcinomas: agonistic effects of progestins and RU-486 mediating rapid non-genomic effects

  • María Cecilia Bottino
  • Juan Pablo Cerliani
  • Paola Rojas
  • Sebastián Giulianelli
  • Rocío Soldati
  • Carolina Mondillo
  • María Alicia Gorostiaga
  • Omar P. Pignataro
  • Juan Carlos Calvo
  • J. Silvio Gutkind
  • Panomwat Amornphimoltham
  • Alfredo A. Molinolo
  • Isabel A. Lüthy
  • Claudia Lanari
Preclinical study

Abstract

In this article, we demonstrate the expression of functional progesterone binding sites at the cell membrane in murine mammary carcinomas that are stimulated by progestins and inhibited by antiprogestins. Using confocal immunofluorescence, ligand binding and cell compartment-specific western blots, we were able to identify the presence of the classical progesterone receptors. Medroxyprogesterone acetate (MPA) and RU-486 (1 × 10−11 and 1 × 10−8 M) behaved as agonists activating extracellular signal-regulated kinases (ERKs) and progestin-regulated proteins, except for Cyclin D1 and Tissue factor which failed to increase with 1 × 10−8 M RU-486, an experimental condition that allows PR to bind DNA. These results predicted a full agonist effect at low concentrations of RU-486. Accordingly, at concentrations lower than 1 × 10−11 M, RU-486 increased cell proliferation in vitro. This effect was abolished by incubation with the ERK kinase inhibitor PD 98059 or by OH-tamoxifen. In vivo, at a daily dose of 1.2 μg/kg body weight RU-486 increased tumor growth, whereas at 12 mg/kg induces tumor regression. Our results indicate that low concentrations of MPA and RU-486 induce similar agonistic non-genomic effects, whereas RU-486 at higher concentrations may inhibit cell proliferation by genomic-induced effects. This suggests that RU-486 should be therapeutically administered at doses high enough to guarantee its genomic inhibitory effect.

Keywords

Membrane progesterone receptors Mammary carcinomas Progesterone receptor isoforms: membrane-initiated steroid signaling Antiprogestins Breast cancer treatment Non-genomic effects Progestins 

Abbreviations

chFCS

Steroid-stripped fetal calf serum

ERα

ER alpha

MISS

Membrane initiated steroid signaling

MPA

Medroxyprogesterone acetate

mPR

Membrane progesterone receptors

OH-Tam

OH-Tamoxifen

PD

PD 98059

Pg

Progesterone

PI

Propidium iodide

PR

Progesterone receptor

PR-A

PR isoform A

PR-B

PR isoform B

s.c

Subcutaneous

Notes

Acknowledgments

This work was supported by Fundación Sales, ANPCyT (PICT 07-932 and PICT 05-38302), CONICET (PIP 5351). Drs. Gutkind, Amornphimoltham and Molinolo are supported by the Intramural Research Program of the Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD. We are very grateful to Dr. Elisa Bal de Kier Joffe for providing LM3 cells, to Julieta Bolado and to Pablo Do Campo for excellent technical assistance, and to Laboratorios Craveri, Buenos Aires for providing MPA depot and to Bayer Schering Pharma AG for the ZK230211. We also wish to thank Avon Foundation for an AACR travel award to MC Bottino and the UICC for an ICRETT fellowship to MC Bottino.

Conflict of interest statement

The authors declare that they have no competing interests.

Supplementary material

Fig. S1

Effects of low concentrations of RU-486 on the proliferation of human breast cancer cells. a T47D cells plated in 96 well plates were starved for 24 h and then treated with RU-486 or MPA for 48 h. 3H-thymidine was added for the last 24 h. 3H-thymidine labeling index was calculated as experimental cpm/control cpm. A representative experiment of three is shown and octuplicates were used for each experimental group; ***: p < 0.001 and *: p < 0.05 between experimental and control group. b Representative western blots of pERKs, pAKT, total ERK and AKT illustrating the increase in ERK and AKT activation in T47D cells treated for 10 min with RU-486. (JPG 261 kb)

10549_2010_971_MOESM1_ESM.jpg (262 kb)
Non-linear regression analysis of Rh6G-CB7 titration curve (JPEG 74 kb)

References

  1. 1.
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839PubMedCrossRefGoogle Scholar
  2. 2.
    Torchia J, Glass C, Rosenfeld MG (1998) Co-activators and co-repressors in the integration of transcriptional responses. Curr Opin Cell Biol 10:373–383PubMedCrossRefGoogle Scholar
  3. 3.
    Bagchi MK, Tsai SY, Weigel NL, Tsai MJ, O’Malley BW (1990) Regulation of in vitro transcription by progesterone receptor. Characterization and kinetic studies. J Biol Chem 265:5129–5134PubMedGoogle Scholar
  4. 4.
    Sutter-Dub MT (2002) Rapid non-genomic and genomic responses to progestogens, estrogens, and glucocorticoids in the endocrine pancreatic B cell, the adipocyte and other cell types. Steroids 67:77–93PubMedCrossRefGoogle Scholar
  5. 5.
    Pietras RJ, Szego CM (1977) Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature 265:69–72PubMedCrossRefGoogle Scholar
  6. 6.
    Cato AC, Nestl A, Mink S (2002) Rapid actions of steroid receptors in cellular signaling pathways. Sci STKE 138:RE9Google Scholar
  7. 7.
    Watson CS, Gametchu B (1999) Membrane-initiated steroid actions and the proteins that mediate them. Proc Soc Exp Biol Med 220:9–19PubMedCrossRefGoogle Scholar
  8. 8.
    Song RX, Fan P, Yue W, Chen Y, Santen RJ (2006) Role of receptor complexes in the extranuclear actions of estrogen receptor alpha in breast cancer. Endocr Relat Cancer 13(Suppl 1):S3–S13PubMedCrossRefGoogle Scholar
  9. 9.
    Ehring GR, Kerschbaum HH, Eder C, Neben AL, Fanger CM, Khoury RM, Negulescu PA, Cahalan MD (1998) A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes. J Exp Med 188:1593–1602PubMedCrossRefGoogle Scholar
  10. 10.
    Grazzini E, Guillon G, Mouillac B, Zingg HH (1998) Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 392:509–512PubMedCrossRefGoogle Scholar
  11. 11.
    Valera S, Ballivet M, Bertrand D (1992) Progesterone modulates a neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci USA 89:9949–9953PubMedCrossRefGoogle Scholar
  12. 12.
    McEwen BS (1991) Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol Sci 12:141–147PubMedCrossRefGoogle Scholar
  13. 13.
    Krebs CJ, Jarvis ED, Chan J, Lydon JP, Ogawa S, Pfaff DW (2000) A membrane-associated progesterone-binding protein, 25-Dx, is regulated by progesterone in brain regions involved in female reproductive behaviors. Proc Natl Acad Sci USA 97:12816–12821PubMedCrossRefGoogle Scholar
  14. 14.
    Labombarda F, Gonzalez SL, Deniselle MC, Vinson GP, Schumacher M, De Nicola AF, Guennoun R (2003) Effects of injury and progesterone treatment on progesterone receptor and progesterone binding protein 25-Dx expression in the rat spinal cord. J Neurochem 87:902–913PubMedCrossRefGoogle Scholar
  15. 15.
    Zhu Y, Bond J, Thomas P (2003) Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc Natl Acad Sci USA 100:2237–2242PubMedCrossRefGoogle Scholar
  16. 16.
    Zhu Y, Rice CD, Pang Y, Pace M, Thomas P (2003) Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA 100:2231–2236PubMedCrossRefGoogle Scholar
  17. 17.
    Dressing GE, Thomas P (2007) Identification of membrane progestin receptors in human breast cancer cell lines and biopsies and their potential involvement in breast cancer. Steroids 72:111–116PubMedCrossRefGoogle Scholar
  18. 18.
    Krietsch T, Fernandes MS, Kero J, Losel R, Heyens M, Lam EW, Huhtaniemi I, Brosens JJ, Gellersen B (2006) Human homologs of the putative G protein-coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone. Mol Endocrinol 20:3146–3164PubMedCrossRefGoogle Scholar
  19. 19.
    Thomas P, Pang Y, Dong J, Groenen P, Kelder J, de Vlieg J, Zhu Y, Tubbs C (2007) Steroid and G protein binding characteristics of the seatrout and human progestin membrane receptor alpha subtypes and their evolutionary origins. Endocrinology 148:705–718PubMedCrossRefGoogle Scholar
  20. 20.
    Molinolo AA, Lanari C, Charreau EH, Sanjuan N, Pasqualini CD (1987) Mouse mammary tumors induced by medroxyprogesterone acetate: immunohistochemistry and hormonal receptors. J Natl Cancer Inst 79:1341–1350PubMedGoogle Scholar
  21. 21.
    Helguero LA, Lamb C, Molinolo AA, Lanari C (2003) Evidence for two progesterone receptor binding sites in murine mammary carcinomas. J Steroid Biochem Mol Biol 84:9–14PubMedCrossRefGoogle Scholar
  22. 22.
    Powell CE, Soto AM, Sonnenschein C (2001) Identification and characterization of membrane estrogen receptor from MCF7 estrogen-target cells. J Steroid Biochem Mol Biol 77:97–108PubMedCrossRefGoogle Scholar
  23. 23.
    Razandi M, Pedram A, Greene GL, Levin ER (1999) Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Mol Endocrinol 13:307–319PubMedCrossRefGoogle Scholar
  24. 24.
    Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER (2002) ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol Endocrinol 16:100–115PubMedCrossRefGoogle Scholar
  25. 25.
    Welter BH, Hansen EL, Saner KJ, Wei Y, Price TM (2003) Membrane-bound progesterone receptor expression in human aortic endothelial cells. J Histochem Cytochem 51:1049–1055PubMedGoogle Scholar
  26. 26.
    Younglai EV, Wu Y, Foster WG, Lobb DK, Price TM (2006) Binding of progesterone to cell surfaces of human granulosa-lutein cells. J Steroid Biochem Mol Biol 101:61–67PubMedCrossRefGoogle Scholar
  27. 27.
    Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E (2004) Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens. Steroids 69:553–559PubMedCrossRefGoogle Scholar
  28. 28.
    Pedram A, Razandi M, Sainson RC, Kim JK, Hughes CC, Levin ER (2007) A conserved mechanism for steroid receptor translocation to the plasma membrane. J Biol Chem 282:22278–22288PubMedCrossRefGoogle Scholar
  29. 29.
    Lanari C, Luthy I, Lamb CA, Fabris V, Pagano E, Helguero LA, Sanjuan N, Merani S, Molinolo AA (2001) Five novel hormone-responsive cell lines derived from murine mammary ductal carcinomas: in vivo and in vitro effects of estrogens and progestins. Cancer Res 61:293–302PubMedGoogle Scholar
  30. 30.
    Dran G, Luthy IA, Molinolo AA, Charreau EH, Pasqualini CD, Lanari C (1995) Effect of medroxyprogesterone acetate (MPA) and serum factors on cell proliferation in primary cultures of an MPA-induced mammary adenocarcinoma. Breast Cancer Res Treat 35:173–186PubMedCrossRefGoogle Scholar
  31. 31.
    Fabris VT, Benavides F, Conti C, Merani S, Lanari C (2005) Cytogenetic findings, Trp53 mutations, and hormone responsiveness in a medroxyprogesterone acetate induced murine breast cancer model. Cancer Genet Cytogenet 161:130–139PubMedCrossRefGoogle Scholar
  32. 32.
    Urtreger A, Ladeda V, Puricelli LI, Rivelli A, Vidal MC, Sacerdote de Lustig E, Bal de Kier Joffe E (1997) Modulation of fibronectin expression and proteolytic activity associated to the invasive and metastatic phenotype in two new murine mammary tumor cell lines. Int J Oncol 11:489–496Google Scholar
  33. 33.
    Clemm DL, Sherman L, Boonyaratanakornkit V, Schrader WT, Weigel NL, Edwards DP (2000) Differential hormone-dependent phosphorylation of progesterone receptor A and B forms revealed by a phosphoserine site-specific monoclonal antibody. Mol Endocrinol 14:52–65PubMedCrossRefGoogle Scholar
  34. 34.
    Lowry OH, Rosebrough NJ, Farr AL (1951) Protein measurements with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  35. 35.
    Kampa M, Nifli AP, Charalampopoulos I, Alexaki VI, Theodoropoulos PA, Stathopoulos EN, Gravanis A, Castanas E (2005) Opposing effects of estradiol- and testosterone-membrane binding sites on T47D breast cancer cell apoptosis. Exp Cell Res 307:41–51PubMedCrossRefGoogle Scholar
  36. 36.
    Lamb CA, Helguero LA, Giulianelli S, Soldati R, Vanzulli SI, Molinolo A, Lanari C (2005) Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice. Breast Cancer Res 7:R1111–R1121PubMedCrossRefGoogle Scholar
  37. 37.
    Lamb C, Simian M, Molinolo A, Pazos P, Lanari C (1999) Regulation of cell growth of a progestin-dependent murine mammary carcinoma in vitro: progesterone receptor involvement in serum or growth factor-induced cell proliferation. J Steroid Biochem Mol Biol 70:133–142PubMedCrossRefGoogle Scholar
  38. 38.
    Giulianelli S, Cerliani JP, Lamb CA, Fabris VT, Bottino MC, Gorostiaga MA, Novaro V, Gongora A, Baldi A, Molinolo A, Lanari C (2008) Carcinoma-associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: a role for the FGF-2/FGFR-2 axis. Int J Cancer 123:2518–2531PubMedCrossRefGoogle Scholar
  39. 39.
    Vanzulli SI, Soldati R, Meiss R, Colombo L, Molinolo AA, Lanari C (2005) Estrogen or antiprogestin treatment induces complete regression of pulmonary and axillary metastases in an experimental model of breast cancer progression. Carcinogenesis 26:1055–1063PubMedCrossRefGoogle Scholar
  40. 40.
    Lanari C, Lamb CA, Fabris VT, Helguero LA, Soldati R, Bottino MC, Giulianelli S, Cerliani JP, Wargon V, Molinolo A (2009) The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer. Endocr Relat Cancer 16:333–350PubMedCrossRefGoogle Scholar
  41. 41.
    Helguero LA, Viegas M, Asaithamby A, Shyamala G, Lanari C, Molinolo AA (2003) Progesterone receptor expression in medroxyprogesterone acetate-induced murine mammary carcinomas and response to endocrine treatment. Breast Cancer Res Treat 79:379–390PubMedCrossRefGoogle Scholar
  42. 42.
    Wargon V, Helguero LA, Bolado J, Rojas P, Novaro V, Molinolo A, Lanari C (2009) Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas. Breast Cancer Res Treat 116:449–460PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang Z, Maier B, Santen RJ, Song RX (2002) Membrane association of estrogen receptor alpha mediates estrogen effect on MAPK activation. Biochem Biophys Res Commun 294:926–933PubMedCrossRefGoogle Scholar
  44. 44.
    Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:719–730PubMedGoogle Scholar
  45. 45.
    Qiu M, Olsen A, Faivre E, Horwitz KB, Lange CA (2003) Mitogen activated protein kinase regulates nuclear association of human progesterone receptors. Mol Endocrinol 17:628–642PubMedCrossRefGoogle Scholar
  46. 46.
    Balana ME, Lupu R, Labriola L, Charreau EH, Elizalde PV (1999) Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas. Oncogene 18:6370–6379PubMedCrossRefGoogle Scholar
  47. 47.
    Carbajal L, Deng J, Dressing GE, Hagan CR, Lange CA, Hammes SR (2009) Meeting review: extra-nuclear steroid receptors-integration with multiple signaling pathways. Steroids 74:551–554PubMedCrossRefGoogle Scholar
  48. 48.
    Quiles I, Millan-Arino L, Subtil-Rodriguez A, Minana B, Spinedi N, Ballare C, Beato M, Jordan A (2009) Mutational analysis of progesterone receptor functional domains in stable cell lines delineates sets of genes regulated by different mechanisms. Mol Endocrinol 23:809–826PubMedCrossRefGoogle Scholar
  49. 49.
    Marino M, Ascenzi P, Acconcia F (2006) S-Palmitoylation modulates estrogen receptor alpha localization and functions. Steroids 71:298–303PubMedCrossRefGoogle Scholar
  50. 50.
    Salatino M, Beguelin W, Peters MG, Carnevale R, Proietti CJ, Galigniana MD, Vedoy CG, Schillaci R, Charreau EH, Sogayar MC, Elizalde PV (2006) Progestin-induced caveolin-1 expression mediates breast cancer cell proliferation. Oncogene 25:7723–7739PubMedCrossRefGoogle Scholar
  51. 51.
    Karteris E, Zervou S, Pang Y, Dong J, Hillhouse EW, Randeva HS, Thomas P (2006) Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol 20:1519–1534PubMedCrossRefGoogle Scholar
  52. 52.
    Bullock LP, Barthe PL, Mowszowicz I, Orth DN, Bardin CW (1975) The effect of progestins on submaxillary gland epidermal growth factor: demonstration of androgenic, synandrogenic and antiandrogenic actions. Endocrinology 97:189–195PubMedCrossRefGoogle Scholar
  53. 53.
    Kontula K, Paavonen T, Luukkainen T, Andersson LC (1983) Binding of progestins to the glucocorticoid receptor. Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes. Biochem Pharmacol 32:1511–1518PubMedCrossRefGoogle Scholar
  54. 54.
    Montecchia MF, Lamb C, Molinolo AA, Luthy IA, Pazos P, Charreau E, Vanzulli S, Lanari C (1999) Progesterone receptor involvement in independent tumor growth in MPA-induced murine mammary adenocarcinomas. J Steroid Biochem Mol Biol 68:11–21PubMedCrossRefGoogle Scholar
  55. 55.
    Horwitz KB, Tung L, Takimoto GS (1996) Novel mechanisms of antiprogestin action. Acta Oncol 35:129–140PubMedCrossRefGoogle Scholar
  56. 56.
    Horwitz KB (1992) The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer? Endocr Rev 13:146–163PubMedGoogle Scholar
  57. 57.
    Labriola L, Salatino M, Proietti CJ, Pecci A, Coso OA, Kornblihtt AR, Charreau EH, Elizalde PV (2003) Heregulin induces transcriptional activation of the progesterone receptor by a mechanism that requires functional ErbB-2 and mitogen-activated protein kinase activation in breast cancer cells. Mol Cell Biol 23:1095–1111PubMedCrossRefGoogle Scholar
  58. 58.
    Carnevale RP, Proietti CJ, Salatino M, Urtreger A, Peluffo G, Edwards DP, Boonyaratanakornkit V, Charreau EH, Bal de Kier JE, Schillaci R, Elizalde PV (2007) Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways. Mol Endocrinol 21:1335–1358PubMedCrossRefGoogle Scholar
  59. 59.
    Skildum A, Faivre E, Lange CA (2005) Progesterone receptors induce cell cycle progression via activation of mitogen-activated protein kinases. Mol Endocrinol 19:327–339PubMedCrossRefGoogle Scholar
  60. 60.
    Arruvito L, Giulianelli S, Flores AC, Paladino N, Barboza M, Lanari C, Fainboim L (2008) NK cells expressing a progesterone receptor are susceptible to progesterone-induced apoptosis. J Immunol 180:5746–5753PubMedGoogle Scholar
  61. 61.
    Park JI, Strock CJ, Ball DW, Nelkin BD (2003) The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway. Mol Cell Biol 23:543–554PubMedCrossRefGoogle Scholar
  62. 62.
    Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185PubMedCrossRefGoogle Scholar
  63. 63.
    Murphy LO, Blenis J (2006) MAPK signal specificity: the right place at the right time. Trends Biochem Sci 31:268–275PubMedCrossRefGoogle Scholar
  64. 64.
    Leonhardt SA, Boonyaratanakornkit V, Edwards DP (2003) Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 68:761–770PubMedCrossRefGoogle Scholar
  65. 65.
    Rowan BG, O’Malley BW (2000) Progesterone receptor coactivators. Steroids 65:545–549PubMedCrossRefGoogle Scholar
  66. 66.
    Dressing GE, Hagan CR, Knutson TP, Daniel AR, Lange CA (2009) Progesterone receptors act as sensors for mitogenic protein kinases in breast cancer models. Endocr Relat Cancer 16:351–361PubMedCrossRefGoogle Scholar
  67. 67.
    Kato S, Pinto M, Carvajal A, Espinoza N, Monso C, Sadarangani A, Villalon M, Brosens JJ, White JO, Richer JK, Horwitz KB, Owen GI (2005) Progesterone increases tissue factor gene expression, procoagulant activity, and invasion in the breast cancer cell line ZR-75-1. J Clin Endocrinol Metab 90:1181–1188PubMedCrossRefGoogle Scholar
  68. 68.
    Owen GI, Richer JK, Tung L, Takimoto G, Horwitz KB (1998) Progesterone regulates transcription of the p21(WAF1) cyclin-dependent kinase inhibitor gene through Sp1 and CBP/p300. J Biol Chem 273:10696–10701PubMedCrossRefGoogle Scholar
  69. 69.
    Cicatiello L, Addeo R, Sasso A, Altucci L, Petrizzi VB, Borgo R, Cancemi M, Caporali S, Caristi S, Scafoglio C, Teti D, Bresciani F, Perillo B, Weisz A (2004) Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. Mol Cell Biol 24:7260–7274PubMedCrossRefGoogle Scholar
  70. 70.
    Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, Shyamala G, Conneely OM, O’Malley BW (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9:2266–2278PubMedCrossRefGoogle Scholar
  71. 71.
    Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA (1995) Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621–630PubMedCrossRefGoogle Scholar
  72. 72.
    Boonyaratanakornkit V, Bi Y, Rudd M, Edwards DP (2008) The role and mechanism of progesterone receptor activation of extra-nuclear signaling pathways in regulating gene transcription and cell cycle progression. Steroids 73:922–928PubMedCrossRefGoogle Scholar
  73. 73.
    Faivre EJ, Daniel AR, Hillard CJ, Lange CA (2008) Progesterone receptor rapid signaling mediates serine 345 phosphorylation and tethering to specificity protein 1 transcription factors. Mol Endocrinol 22:823–837PubMedCrossRefGoogle Scholar
  74. 74.
    Hoffman B, Liebermann DA (2008) Apoptotic signaling by c-MYC. Oncogene 27:6462–6472PubMedCrossRefGoogle Scholar
  75. 75.
    Dressing GE, Lange CA (2009) Integrated actions of progesterone receptor and cell cycle machinery regulate breast cancer cell proliferation. Steroids 74:573–576PubMedCrossRefGoogle Scholar
  76. 76.
    Faivre EJ, Lange CA (2007) Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells. Mol Cell Biol 27:466–480PubMedCrossRefGoogle Scholar
  77. 77.
    Klijn JG, Setyono-Han B, Foekens JA (2000) Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer. Steroids 65:825–830PubMedCrossRefGoogle Scholar
  78. 78.
    Gaddy VT, Barrett JT, Delk JN, Kallab AM, Porter AG, Schoenlein PV (2004) Mifepristone induces growth arrest, caspase activation, and apoptosis of estrogen receptor-expressing, antiestrogen-resistant breast cancer cells. Clin Cancer Res 10:5215–5225PubMedCrossRefGoogle Scholar
  79. 79.
    Moore MR (2004) A rationale for inhibiting progesterone-related pathways to combat breast cancer. Curr Cancer Drug Targets 4:183–189PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • María Cecilia Bottino
    • 1
  • Juan Pablo Cerliani
    • 1
  • Paola Rojas
    • 1
  • Sebastián Giulianelli
    • 1
  • Rocío Soldati
    • 1
  • Carolina Mondillo
    • 1
  • María Alicia Gorostiaga
    • 1
  • Omar P. Pignataro
    • 3
  • Juan Carlos Calvo
    • 3
  • J. Silvio Gutkind
    • 4
  • Panomwat Amornphimoltham
    • 4
  • Alfredo A. Molinolo
    • 4
  • Isabel A. Lüthy
    • 2
  • Claudia Lanari
    • 1
  1. 1.Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas—CONICETBuenos AiresArgentina
  2. 2.Laboratorio de Hormonas y Cáncer, Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas—CONICETBuenos AiresArgentina
  3. 3.Departamento de Química Biológica, Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos AiresBuenos AiresArgentina
  4. 4.Oral and Pharyngeal Cancer BranchNational Institute of Dental and Craniofacial Research National Institutes of HealthBethesdaUSA

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