Skip to main content

Advertisement

SpringerLink
Log in

Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The purpose of this article is to determine the tumorigenic potential of estradiol treatment (E2) when combined with either progesterone (P4) or medroxyprogesterone acetate (MPA) in normal luminal human breast cells (HBE) and in human breast cancer cells (T47-D, MCF-7). Proliferation profiles were evaluated, along with the gene transactivation activity between the progesterone and glucocorticoid receptors (PR, GR) in HBE, T47-D, and MCF-7 cells treated by E2 + P4 or E2 + MPA. High throughput transcriptome analysis was performed on RNA from HBE cells treated by E2, E2 + MPA and E2 + P4. GR content was analyzed in normal breast cells as well. In HBE cells, E2 + P4 treatment was antiproliferative and promoted cellular differentiation. In contrast, E2 + MPA displayed mitogenic, antiapoptotic effects in HBE cells and did not influence cellular differentiation. The effect of P4 and MPA on cell proliferation was, however, variable in breast cancer cells. In cells containing GR or/and PR, MPA decreased proliferation whereas P4 antiproliferative effect needed the presence of PR. In HBE cells, the regulation of genes by E2 + P4, and E2 + MPA was significantly different, particularly in cell proliferation and cell death gene families. Further analysis revealed a modulation of the glucocorticoid receptor gene expression pathway by E2 + MPA. Predominant MPA glucocorticoid activity in normal and breast cancer cells was demonstrated using a glucocorticoid antagonist and the down-regulation of the GR by RNA interference. In normal luminal breast cells and in breast cancer cells, P4 and MPA combined with E2 treatment have opposing mitogenic effects due to GR. The consequences of MPA glucocorticoid potencies as well as the importance of GR in breast tissue merit a reappraisal.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Rossouw JE, Anderson GL, Prentice RL et al (2002) Risks and benefits of estrogen plus progestogen in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333

    Article  PubMed  CAS  Google Scholar 

  2. Fournier A, Berrino F, Clavel-Chapelon F (2008) Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 107:103–111

    Article  PubMed  CAS  Google Scholar 

  3. Bakken K, Fournier A, Lund E et al (2011) Menopausal hormone therapy and breast cancer risk: Impact of different treatments. The European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 128:144–156

    Article  PubMed  CAS  Google Scholar 

  4. Calle EE, Feigelson HS, Hildebrand JS et al (2009) Postmenopausal hormone use and breast cancer associations differ by hormone regimen and histologic subtype. Cancer 115:936–945

    Article  PubMed  CAS  Google Scholar 

  5. Sitruk-Ware R (2008) Pharmacological profile of progestogens. Maturitas 61:151–157

    Article  PubMed  Google Scholar 

  6. Wood CE, Register TC, Lees CJ et al (2007) Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat 101:125–134

    Article  PubMed  CAS  Google Scholar 

  7. Wood CE, Register TC, Cline JM (2009) Transcriptional profiles of progestogen effects in the postmenopausal breast. Breast Cancer Res Treat 114:233–242

    Article  PubMed  CAS  Google Scholar 

  8. Wan Y, Nordeen SK (2002) Overlapping but distinct gene regulation profiles by glucocorticoids and progestogens in human breast cancer cells. Mol Endocrinol 16:1204–1214

    Article  PubMed  CAS  Google Scholar 

  9. Hermes GL, Delgado B, Tretiakova M et al (2009) Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors. Proc Natl Acad Sci USA 106:22393–22398

    Article  PubMed  CAS  Google Scholar 

  10. Moutsatsou P, Papavassiliou AG (2008) The glucocorticoid receptor signalling in breast cancer. J Cell Mol Med 12:145–163

    Article  PubMed  CAS  Google Scholar 

  11. TKaSR Amsterdam A (2002) Cell-specific regulation of apoptosis by glucocorticoids: implication to their anti-inflammatory action. Biochem Pharmacol 64:843–850

    Article  Google Scholar 

  12. Lippman M, Bolan G, Huff K (1976) The effects of glucocorticoids and progesterone on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 36:4602–4609

    PubMed  CAS  Google Scholar 

  13. Belova L, Delgado B, Kocherginsky M, Melhem A, Olopade OI, Conzen SD (2009) Glucocorticoid receptor expression in breast cancer associates with older patient age. Breast Cancer Res Treat 116:441–447

    Article  PubMed  CAS  Google Scholar 

  14. Malet C, Gompel A, Yaneva H et al (1991) Estradiol and progesterone receptors in cultured normal human breast epithelial cells and fibroblasts: immunocytochemical studies. J Clin Endocrinol Metab 73:8–17

    Article  PubMed  CAS  Google Scholar 

  15. Malet C, Gompel A, Spritzer P et al (1988) Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture. Cancer Res 48:7193–7199

    PubMed  CAS  Google Scholar 

  16. Cavailles V, Gompel A, Portois MC et al (2002) Comparative activity of pulsed or continuous estradiol exposure on gene expression and proliferation of normal and tumoral human breast cells. J Mol Endocrinol 28:165–175

    Article  PubMed  CAS  Google Scholar 

  17. Rochefort H (1995) Oestrogen- and anti-oestrogen-regulated genes in human breast cancer. Ciba Found Symp 191:254–265 (discussion 265–258)

    PubMed  CAS  Google Scholar 

  18. May FE, Johnson MD, Wiseman LR et al (1989) Regulation of progesterone receptor mRNA by oestradiol and antioestrogens in breast cancer cell lines. J Steroid Biochem 33:1035–1041

    Article  PubMed  CAS  Google Scholar 

  19. Westley B, May FE, Brown AM et al (1984) Effects of antiestrogens on the estrogen-regulated pS2 RNA and the 52- and 160-kilodalton proteins in MCF7 cells and two tamoxifen-resistant sublines. J Biol Chem 259:10030–10035

    PubMed  CAS  Google Scholar 

  20. Gompel A, Malet C, Spritzer P et al (1986) Progestogen effect on cell proliferation and 17 beta-hydroxysteroid dehydrogenase activity in normal human breast cells in culture. Journal Clin Endocrinol Metab 63:1174–1180

    Article  CAS  Google Scholar 

  21. Svensson LO, Johnson SH, Olsson SE (1994) Plasma concentrations of medroxyprogesterone acetate, estradiol and estrone following oral administration of Klimaxil, Trisequence/Provera and Divina. A randomized, single-blind, triple cross-over bioavailability study in menopausal women. Maturitas 18:229–238

    Article  PubMed  CAS  Google Scholar 

  22. Somai S, Chaouat M, Jacob D et al (2003) Antiestrogens are pro-apoptotic in normal human breast epithelial cells. Int J Cancer 105:607–612

    Article  PubMed  CAS  Google Scholar 

  23. Chalbos D, Joyeux C, Galtier F et al (1992) Progestogen-induced fatty acid synthetase in human mammary tumors: from molecular to clinical studies. J Steroid Biochem Mol Biol 43:223–228

    Article  PubMed  CAS  Google Scholar 

  24. Kuhajda FP (2006) Fatty acid synthase and cancer: new application of an old pathway. Cancer Res 66:5977–5980

    Article  PubMed  CAS  Google Scholar 

  25. Esslimani-Sahla M, Thezenas S, Simony-Lafontaine J, Kramar A, Lavaill R, Chalbos D, Rochefort H (2007) Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis. Int J Cancer 120:224–229

    Article  PubMed  CAS  Google Scholar 

  26. Poulin R, Baker D, Poirier D et al (1991) Multiple actions of synthetic ‘progestogens’ on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestogen, estrogen, and glucocorticoid agonistic and antagonistic activities of steroids. Breast Cancer Res Treat 17:197–210

    Article  PubMed  CAS  Google Scholar 

  27. Karst H, de Kloet ER, Joels M (1997) Effect of ORG 34116, a corticosteroid receptor antagonist, on hippocampal Ca2+ currents. Eur J Pharmacol 339:17–26

    Article  PubMed  CAS  Google Scholar 

  28. Attardi BJ, Burgenson J, Hild SA et al (2004) In vitro antiprogestational/antiglucocorticoid activity and progestogen and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone. J Steroid Biochem Mol Biol 88:277–288

    Article  PubMed  CAS  Google Scholar 

  29. Lien HC, Lu YS, Cheng AL, Chang WC, Jeng YM, Kuo YH, Huang CS, Chang KJ, Yao YT (2006) Differential expression of glucocorticoid receptor in human breast tissues and related neoplasms. J Pathol 209:317–327

    Article  PubMed  CAS  Google Scholar 

  30. Conde IP, FraileB Lucio J, Arenas MI (2008) Glucocorticoid receptor changes its cellular location with breast cancer development. Histol Histopathol 23:77–85

    PubMed  CAS  Google Scholar 

  31. Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  PubMed  CAS  Google Scholar 

  32. Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  PubMed  CAS  Google Scholar 

  33. Richardson AL, Wang ZC, De Nicolo A et al (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9:121–132

    Article  PubMed  CAS  Google Scholar 

  34. Boersma BJ, Reimers M, Yi M et al (2008) A stromal gene signature associated with inflammatory breast cancer. Int J Cancer 122:1324–1332

    Article  PubMed  CAS  Google Scholar 

  35. Bonnefoi H, Potti A, Delorenzi M et al (2007) Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. Lancet Oncol 8:1071–1078

    Article  PubMed  CAS  Google Scholar 

  36. Chin K, DeVries S, Fridlyand J et al (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10:529–541

    Article  PubMed  CAS  Google Scholar 

  37. Loi S, Haibe-Kains B, Desmedt C et al (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25:1239–1246

    Article  PubMed  CAS  Google Scholar 

  38. Loi S, Haibe-Kains B, Desmedt C et al (2008) Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics 9:239

    Article  PubMed  Google Scholar 

  39. Sotiriou C, Neo SY, McShane LM et al (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100:10393–10398

    Article  PubMed  CAS  Google Scholar 

  40. Yu K, Ganesan K, Miller LD et al (2006) A modular analysis of breast cancer reveals a novel low-grade molecular signature in estrogen receptor-positive tumors. Clin Cancer Res 12:3288–3296

    Article  PubMed  CAS  Google Scholar 

  41. Gompel A, Somaï S, Chaouat M et al (2000) Hormonal regulation of apoptosis in breast cells and tissues. Steroids 65:593–598

    Article  PubMed  CAS  Google Scholar 

  42. Foidart JM, Colin C, Denoo X et al (1998) Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 69:963–969

    Article  PubMed  CAS  Google Scholar 

  43. Hofseth LJ, Raafat AM, Osuch JR et al (1999) Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 84:4559–4565

    Article  PubMed  CAS  Google Scholar 

  44. Wintermantel TM, Bock D, Fleig V, Greiner EF, Schutz G (2005) The epithelial glucocorticoid receptor is required for the normal timing of cell proliferation during mammary lobuloalveolar development but is dispensable for milk production. Mol Endocrinol 19:340–349

    Article  PubMed  CAS  Google Scholar 

  45. Leo JC, Guo C, Woon CT et al (2004) Glucocorticoid and mineralocorticoid cross-talk with progesterone receptor to induce focal adhesion and growth inhibition in breast cancer cells. Endocrinology 145:1314–1321

    Article  PubMed  CAS  Google Scholar 

  46. Szapary D, Song LN, He Y et al (2008) Differential modulation of glucocorticoid and progesterone receptor transactivation. Mol Cell Endocrinol 283:114–126

    Article  PubMed  CAS  Google Scholar 

  47. Foidart JM, Desreux J, Pintiaux A et al (2007) Hormone therapy and breast cancer risk. Climacteric 10(Suppl 2):54–61

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Drs. Michèle Resche-Rigon (HRA Pharma, Paris) for helpful discussions and providing the anti-progestogen VA-2914, Steve K. Nordeen (University of Colorado, Denver) for kindly providing sequences of IEX-1 primers, Helenius J. Kloosterboer (Organon, Part of Shering-Plough, Oss) for providing antiglucocorticoid ORG-34116, Ramiro Castro Urology Medical Director (GSK, UK) for the generous gift of Dutasteride and Sylvie Dumont for her excellent technical assistance in immunohistochemistry experiments. We are grateful to Niel Insdorf for his kind help in editing the manuscript. This research was supported by grants from INSERM-UPMC, the Association pour la Recherche sur le Cancer, HRA Pharma and Novartis (France). Aurélie Courtin was a recipient of a grant from the Association pour la Recherche sur le Cancer, Laudine Communal is a recipient for a grant from HRA Pharma. Myriam Vilasco is a recipient of a post-doc fellowship (Institut National Contre le Cancer-INCA). Daniela Taverna was supported by grants from the University of Torino (Local Research Funding 2007/DT, 2008/DT), Regione Piemonte Ricerca Scientifica Applicata (CIPE2004/DT) and Compagnia di San Paolo, Torino. Daniela Cimino is a fellow of the Regione Piemonte.

Author information

Authors and Affiliations

  1. INSERM-UPMC, UMRS 938, Hôpital Saint-Antoine, Paris, France

    Aurélie Courtin, Laudine Communal, Myriam Vilasco, Najat Mourra, Patricia Forgez & Anne Gompel

  2. Center for Molecular Systems Biology and Department of Oncological Sciences, University of Torino, c/o Institute for Cancer Research and Treatment (IRCC), Candiolo, Italy

    Daniela Cimino, Michele de Bortoli & Daniela Taverna

  3. Molecular Biotechnology Center, University of Torino, Turin, Italy

    Daniela Cimino & Daniela Taverna

  4. Service d’Anatomie et Cytologie Pathologiques, AP-HP, Hôpital Saint-Antoine, Paris, France

    Najat Mourra

  5. Plateforme de Cytométrie, IFR 65-St Antoine UMPC, Paris, Farnce

    Anne-Marie Faussat

  6. Université Paris Diderot, AP-HP, Hôpital Saint-Louis, Service de Chirurgie Plastique, Paris, France

    Marc Chaouat

  7. Université Paris Descartes, AP-HP, Hôtel-Dieu, UF de Gynécologie, 1 Place du Parvis Notre-Dame, 75004, Paris, France

    Anne Gompel

Authors
  1. Aurélie Courtin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laudine Communal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Myriam Vilasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniela Cimino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Najat Mourra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michele de Bortoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniela Taverna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne-Marie Faussat
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marc Chaouat
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Patricia Forgez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anne Gompel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne Gompel.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10549_2011_1394_MOESM1_ESM.ppt

Supplementary Figure 1: Validation of HBE cell model: PR and ER protein expression. Immunocytochemistry of PR (left) and ER (right) and negative control (NC) (a) (original magnification ×200). Characterization of luminal epithelial cells using expression of CK18 detected by immunofluorescence (b) (original magnification ×600). Comparison of PR and ER mRNA amounts in normal and breast cancer cells by RT-qPCR (c). Results are expressed in cycle threshold (Ct) values (mean ± SEM, n = 5 (HBE), n = 3 (MCF-7 and T47-D))

Rights and permissions

Reprints and permissions

About this article

Cite this article

Courtin, A., Communal, L., Vilasco, M. et al. Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells. Breast Cancer Res Treat 131, 49–63 (2012). https://doi.org/10.1007/s10549-011-1394-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1394-5

Keywords

Search

Navigation