Skip to main content
SpringerLink
Log in

Progesterone Receptors in Mammary Gland Development and Tumorigenesis

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The steroid hormone, progesterone (P), is a central coordinator of all aspects of female reproductive activity and plays a key role in pregnancy-associated mammary gland morphogenesis and mammary tumorigenesis. The effects of P on the mammary gland are mediated by two structurally and functionally distinct nuclear receptors PR-A and PR-B that arise from a single gene. Null mutation of both receptors in PR knockout (PRKO) mice has demonstrated a critical role for PRs in mediating pregnancy-associated mammary ductal branching and lobuloalveolar differentiation and in initiation of mammary tumors in response to carcinogen. Analysis of the molecular genetic pathways disrupted in PRKO mice has recently yielded important insights into the molecular mechanisms of regulation of mammary gland morphogenesis by PRs. In addition to its essential role in regulating proliferative and differentiative responses of the adult mammary gland during pregnancy, P plays a critical role in the protection against mammary tumorigenesis afforded by early parity. Thus, the effects of P on postnatal developmental plasticity of the mammary gland differ between young and adult glands. This review will summarize recent advances in our understanding of 1) the molecular mechanisms by which PRs mediate pregnancy-associated mammary gland morphogenesis, 2) the role of PRs in mediating tumorigenic responses of the adult mammary gland to carcinogen, and 3) the role of P in long-term protection of the juvenile mammary gland against tumorigenesis. In addition, we will summarize recent insights into the isoform selective contributions to some of these activities of PRs obtained from comparative analysis of P-dependent mammary gland development in PR isoform specific knockout mice lacking either the PR-A (PRAKO) or PR-B (PRBKO).

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

Similar content being viewed by others

REFERENCES

  1. R. D. Cardiff (2001). Validity of mouse mammary tumour models for human breast cancer: Comparative pathology. Microsc. Res. Tech. 52:224–230.

    PubMed  Google Scholar 

  2. J. R. Harris, M. E. Lippman, U. Veronesi, and W. Willett (1992). Breast cancer (1). N. Engl. J. Med. 327:319–328.

    PubMed  Google Scholar 

  3. B. E. Henderson, R K. Ross, and M. C. Pike (1991). Toward the primary prevention of cancer. Science 254:1131–1138.

    PubMed  Google Scholar 

  4. J. L. Kelsey and M. D. Gammon (1991). The epidemiology of breast cancer. CA: Cancer J. Clin. 41:146–165.

    PubMed  Google Scholar 

  5. L. A. Loeb (2001). Amutator phenotype in cancer. Cancer Res. 61:3230–3239.

    PubMed  Google Scholar 

  6. D. V. Spicer, E. A. Krecker, and M. C. Pike (1995). The endocrine prevention of breast cancer. Cancer Invest. 13:495–504.

    PubMed  Google Scholar 

  7. S. P. Robinson and V. C. Jordan (1987). Reversal of antitumor effects of tamoxifen by progesterone in the 7, 12-dimethylbenzanthracene-induced rat mammary carcinoma model. Cancer Res. 47:5386–5390.

    PubMed  Google Scholar 

  8. H. Nagasawa, M. Aoki, N. Sakagami, and M. Ishida (1988). Medroxyprogesterone acetate enhances spontaneous mammary tumorigenesis and uterine adenomyosis in mice. Breast Cancer Res. Treat. 12:59–66.

    PubMed  Google Scholar 

  9. B. S. McEwen (1991). Non-genomic and genomic effects of steroids on neural activity. Trends Pharmacol. Sci. 12:141–147.

    PubMed  Google Scholar 

  10. C. Schairer, J. Lubin, R. Troisi, S. Sturgeon, L. Brinton, and R. Hoover (2000). Estrogen-progestin replacement and risk of breast cancer. JAMA 284:691–694.

    Google Scholar 

  11. L. Sivaraman and D. Medina (2002). Hormone-induced protection against breast cancer. J. Mammary Gland Biol. Neoplasia 7:77–92.

    PubMed  Google Scholar 

  12. D. Medina, L. Sivaraman, S. G. Hilsenbeck, O. Conneely, M. Ginger, J. Rosen, et al. (2001). Mechanisms of hormonal prevention of breast cancer. Ann. N. Y. Acad. Sci. 952:23–35.

    PubMed  Google Scholar 

  13. L. Sivaraman, O. M. Conneely, D. Medina, and B. W. O'Malley (2001). p53 is a potential mediator of pregnancy and hormoneinduced resistance to mammary carcinogenesis. Proc. Natl. Acad. Sci. U. S. A. 98:12379–12384.

    PubMed  Google Scholar 

  14. S. M. Swanson, R. C. Guzman, G. Collins, P. Tafoya, G. Thordarson, F. Talamantes, et al. (1995). Refractoriness to mammary carcinogenesis in the parous mouse is reversible by hormonal stimulation induced by pituitary isografts. Cancer Lett. 90:171–181.

    PubMed  Google Scholar 

  15. S. A. Onate, S. Y. Tsai, M. J. Tsai, and B. W. O'Malley (1995). Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270:1354–1357.

    PubMed  Google Scholar 

  16. H. Gronemeyer (1991). Transcription activation by estrogen and progesterone receptors. Annu. Rev. Genet. 25:89–123.

    PubMed  Google Scholar 

  17. Y. Kamei, L. Xu, T. Heinzel, J. Torchia, R. Kurokawa, B. Gloss, et al. (1996). A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85:403–414.

    PubMed  Google Scholar 

  18. S. Y. Tsai, J. Carlsedt-Duke, N. L. Weigel, K. Dahlman, J. A. Gustafsson, M. J. Tsai, et al. (1988). Molecular interactions of steroid hormone receptor with its enhancer element: Evidence for receptor dimer formation. Cell 55:361–369.

    PubMed  Google Scholar 

  19. G. F. Allan, X. H. Leng, S. Y. Tsai, N. L. Weigel, D. P. Edwards, M.-J. Tsai, et al. (1992). Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation. J. Biol. Chem. 267:19513–19520.

    PubMed  Google Scholar 

  20. M. E. Meyer, C. Quirin-Stricker, T. Lerouge, M. T. Bocquel, and H. Gronemeyer (1992). A limiting factor mediates the differential activation of promoters by the human progesterone receptor isoforms. J. Biol. Chem. 267:10882–10887.

    PubMed  Google Scholar 

  21. C. A. Sartorius, M. Y. Melville, A. R. Hovland, L. Tung, G. S. Takimoto, and K. B. Horwitz (1994). A third transactivation function (AF3) of human progesterone receptors located in the unique N-terminal segment of the B-isoform. Mol. Endocrinol. 8:1347–1360.

    PubMed  Google Scholar 

  22. P. H. Giangrande, E. A. Kimbrel, D. P. Edwards, and D. P. McDonnell (2000). The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol. Cell. Biol. 20:3102–3115.

    PubMed  Google Scholar 

  23. L. Tora, H. Gronemeyer, B. Turcotte, M. P. Gaub, and P. Chambon (1988). The N-terminal region of the chicken progesterone receptor specifies target gene activation. Nature 333:185–188.

    PubMed  Google Scholar 

  24. E. Vegeto, M. M. Shahbaz, D. X. Wen, M. E. Goldman, B. W. O'Malley, and D. P. McDonnell (1993). Human progesterone receptor A form is a cell and promoter specific repressor of human progesterone receptor B function. Mol. Endocrinol. 7:1244–1255.

    PubMed  Google Scholar 

  25. M. Breckwoldt, C. Keck, and U. Karack (1995). Benefits and risks of hormone replacement therapy (HRT). J. Steroid Biochem. Mol. Biol. 53:205–208.

    PubMed  Google Scholar 

  26. A. R. Hovland, R. L. Powell, G. S. Takimoto, L. Tung, and K. B. Horwitz (1998). An N-terminal inhibitory function, IF, suppresses transcription by the A-isoform but not the B-isoform of human progesterone receptors. J. Biol. Chem. 273:5455–5460.

    PubMed  Google Scholar 

  27. E. M. McGowan and C. L. Clarke (1999). Effect of overexpression of progesterone receptor A on endogenous progestinsensitive endpoints in breast cancer cells. Mol. Endocrinol. 13:1657–1671.

    PubMed  Google Scholar 

  28. J. K. Richer, B. M. Jacobsen, N. G. Manning, M. G. Abel, D. M. Wolf, and K. B. Horwitz (2002). Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J. Biol. Chem. 277:5209–5218.

    PubMed  Google Scholar 

  29. P. A. Mote, R. L. Balleine, E. M. McGowan, and C. L. Clarke (1999). Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle. J. Clin. Endocrinol. Metab. 84:2963–2971.

    PubMed  Google Scholar 

  30. R. L. Arnett-Mansfield, A. deFazio, G. V. Wain, R. C. Jaworski, K. Byth, P. A. Mote, et al. (2001). Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium. Cancer Res. 61:4576–4582.

    PubMed  Google Scholar 

  31. R. K. Mangal, R. D. Wiehle, A. N. Poindexter, 3rd, and N. L. Weigel (1997). Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle. J. Steroid Biochem. Mol. Biol. 63:195–202.

    PubMed  Google Scholar 

  32. P A. Mote, R. L. Balleine, E. M. McGowan, and C. L. Clarke (2000). Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma. Hum. Reprod. 15(Suppl. 3)48–56.

    PubMed  Google Scholar 

  33. M. J. Tetel, P. H. Giangrande, S. A. Leonhardt, D. P. McDonnell, and D. P. Edwards (1999). Hormone-dependent interaction between the amino-and carboxyl-terminal domains of progesterone receptor in vitro and in vivo. Mol. Endocrinol. 13:910–924.

    PubMed  Google Scholar 

  34. J. P. Lydon, F. J. DeMayo, C. R. Funk, S. K. Mani, A. R. Hughes, C. A. MontgomeryJr., et al. (1995). Mice lacking progesterone receptors exhibit pleiotropic reproductive abnormalities. Genes Dev. 9:2266–2278.

    PubMed  Google Scholar 

  35. S. K. Mani, J. M. C. Allen, J. P. Lydon, B. Mulac-Jericevic, J. D. Blaustein, F. J. DeMayo, et al. (1996). Dopamine requires the unoccupied progesterone receptor to induce sexual behavior in mice. Mol. Endocrinol. 10:1728–1737.

    PubMed  Google Scholar 

  36. P. E. Chappell, J. P. Lydon, O. M. Conneely, B. W. O'Malley, and J. E. Levine (1997). Endocrine defects in mice carrying a null mutation for the progesterone receptor gene. Endocrinology 138:4147–4152.

    PubMed  Google Scholar 

  37. P. Chappell, J. S. Schneider, P. Kim, M. Xu, J. P. Lydon, B. W. O'Malley, et al. (1999). Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (ovx), estrogen (E2)-treated, progesterone receptor knockout (PRKO) mice. Endocrinology 140:3653–3658.

    PubMed  Google Scholar 

  38. O. M. Conneely, D. M. Kettelberger, M.-J. Tsai, W. T. Schrader, and B. W. O'Malley (1989). The chicken progesterone receptor A and B isoforms are products of an alternate translation initiation event. J. Biol. Chem. 264:14062–14064.

    PubMed  Google Scholar 

  39. P. Kastner, A. Krust, B. Turcotte, U. Strupp, L. Tora, H. Gronemeyer, et al. (1990). Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO. J. 9:1603–1614.

    PubMed  Google Scholar 

  40. P. H. Giangrande, G. Pollio, and D. P. McDonnell (1997). Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor. J. Biol. Chem. 272:32889–32900.

    PubMed  Google Scholar 

  41. B. Mulac-Jericevic, R. A. Mullinax, F. J. DeMayo, J. P. Lydon, and O. M. Conneely (2000). Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 289:1751–1754.

    PubMed  Google Scholar 

  42. C. Brisken, S. Park, T. Vass, J. P. Lydon, B. W. O'Malley, and R. A. Weinberg (1998). A paracrine role for the epithelial progesterone receptor inmammarygland development. Proc. Natl. Acad. Sci. U. S. A. 95:5076–5081.

    PubMed  Google Scholar 

  43. T. N. Seagroves, J. P. Lydon, R. C. Hovey, B. K. Vonderhaar, and J. M. Rosen (2000). C/EBPb(CCAAT/Enhancer Binding Protein) controls cell fate determination during mammary gland development. Mol. Endocrinol. 14:359–368.

    PubMed  Google Scholar 

  44. L. Sivaraman, S. G. Hilsenbeck, L. Zhong, J. Gay, O. M. Conneely, D. Medina, et al. (2001). Early exposure of the rat mammary gland to estrogen and progesterone blocks colocalization of estrogen receptor expression and proliferation. J. Endocrinol. 171:75–83.

    PubMed  Google Scholar 

  45. P. M. Ismail, J. Li, F. J. DeMayo, B. W. O'Malley, and J. P. Lydon (2002). A novel LacZ reporter mouse reveals complex regulation of the progesterone receptor promoter during mammary gland development. Mol. Endocrinol. 16:2475–2489.

    PubMed  Google Scholar 

  46. S. L. Grimm, T. N. Seagroves, E. B. Kabotyanski, R. C. Hovey, B. K. Vonderhaar, J. P. Lydon, et al. (2002). Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development. Mol. Endocrinol. 16:2675–2691.

    PubMed  Google Scholar 

  47. R. B. Clarke, A. Howell, C. S. Potten, and E. Anderson (1997). Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 57:4987–4991.

    PubMed  Google Scholar 

  48. C. Brisken, A. Heineman, T. Chavarria, B. Elenbaas, J. Tan, S. K. Dey, et al. (2000). Essential function of Wnt-4 in mammarygland development downstream of progesterone signaling. Genes Dev. 14:650–654.

    PubMed  Google Scholar 

  49. P. A. Kelly, A. Bachelot, C. Kedzia, L. Hennighausen, C. J. Ormandy, J. J. Kopchick, et al. (2002). The role of prolactin and growth hormone in mammary gland development. Mol. Cell. Endocrinol. 197:127–131.

    PubMed  Google Scholar 

  50. C. Brisken, A. Ayyannan, C. Nguyen, A. Heineman, F. Reinhardt, T. Jan, et al. (2002). IGF-2 is a mediator of prolactininduced morphogenesis in the breast. Dev. Cell 3:877–887.

    PubMed  Google Scholar 

  51. P. Sicinski, J. L. Donaher, S. B. Parker, T. Li, A, Fazeli, H. Gardner, et al. (1995). Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621–630.

    PubMed  Google Scholar 

  52. W. P. Bocchinfuso and K. S. Korach (1997). Mammary gland development and tumorigenesis in estrogen receptor knockout mice. J. Mam. Gland Biol. Neoplasia 2:323–334.

    Google Scholar 

  53. V. Fantl, P. A. W. Edwards, J. H. Steel, B. K. Vonderhaar, and C. Dickson (1999). Impaired mammary gland development in cyl-1-/-mice during pregnancy and lactation is epithelial cell autonomous. Dev. Biol. 212:1–11.

    PubMed  Google Scholar 

  54. G. Shyamala, X. Yang, G. Silberstein, M. H. Barcellos-Hoff, and E. Dale (1998). Transgenic mice carrying an imbalance in the native-ratio of A to B forms of progesterone receptor exhibit developmental abnormalities in mammary glands. Proc. Natl. Acad. Sci. U. S. A. 95:696–701.

    PubMed  Google Scholar 

  55. G. B. Silberstein, K. Van Horn, G. Shyamala, and C. W. Daniel (1996). Progesterone receptors in the mouse mammary duct: Distribution and developmental regulation. Cell Growth Differ. 7:945–952.

    PubMed  Google Scholar 

  56. J. P. Lydon, G. Ge, F. S. Kittrell, D. Medina, and B. W. O'Malley (1999). Murine mammary gland carcinogenesis is critically dependent on progesterone receptor function. Cancer Res. 59:4276–4284.

    PubMed  Google Scholar 

  57. S. Soyal, P. M. Ismail, J. Li, B. Mulac-Jericevic, O. M. Conneely, and J. P. Lydon (2002). Progesterone's role in mammary gland development and tumorigenesis as disclosed by experimental mouse genetics. Breast Cancer Res. 4:191–196.

    PubMed  Google Scholar 

  58. R. T. Chatterton, Jr., J. P. Lydon, R. G. Mehta, E. T. Mateo, A. Pletz, and V. C. Jordan (2002). Role of the progesterone receptor (PR) in susceptibility of mouse mammary gland to 7, 12-dimethylbenz[a]anthracene-induced hormoneindependent preneoplastic lesions in vitro. Cancer Lett. 188:47–52.

    PubMed  Google Scholar 

  59. R. K. Ross, A. Paganini-Hill, P. C. Wan, and M. C. Pike (2000). Effect of hormone replacement therapy on breast cancer risk: Estrogen versus estrogen plus progestin. J. Natl. Cancer Inst. 92:328–332.

    PubMed  Google Scholar 

  60. R. Sitruk-Ware (2002). Progestogens in hormal replacement therapy: New molecules, risks, and benefits. Menopause: J. North Am. Menopause Soc. 9:6–15.

    Google Scholar 

  61. P. A. Mote, S. Bartow, N. Tran, and C. L. Clarke (2002). Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis. Breast Cancer Res. Treat. 72:163–172.

    PubMed  Google Scholar 

  62. J. D. Graham, C. Yeates, R. L. Balleine, S. S. Harvey, J. S. Milliken, A. M. Bilous, et al. (1995). Characterization of progesterone receptor A and B expression in human breast cancer. Cancer Res. 55:5063–5068.

    PubMed  Google Scholar 

  63. G. Shyamala, X. Yang, R. D. Cardiff, and E. Dale (2000). Impact of progesterone receptor on cell-fate decisions during mammary gland development. Proc. Natl. Acad. Sci. U. S. A. 97:3044–3049.

    PubMed  Google Scholar 

  64. E. C. Hirsch, M. G. A. and Y. Agid (1989). Selective vulnerability of pigmented dopaminergic neurons in Parkinson's disease. Acta Neurol. Scand. Suppl. 126:19–22.

    PubMed  Google Scholar 

  65. E. Marshal (1993). Search for a killer: Focus shifts from fat to hormones. Science 259:618–621.

    PubMed  Google Scholar 

  66. K. U. Wagner, C. A. Boulanger, M. D. Henry, M. Sgagias, L. Hennighausen, and G. H. Smith (2002). An adjunct mammary epithelial cell population in parous females: Its role in functional adaptation and tissue renewal. Development 129:1377–1386.

    PubMed  Google Scholar 

  67. M. R. Ginger, M. F. Gonzalez-Rimbau, J. P. Gay, and J. M. Rosen (2001). Persistent changes in gene expression induced by estrogen and progesterone in the rat mammary gland. Mol. Endocrinol. 15:1993–2009.

    PubMed  Google Scholar 

  68. C. M. D'Cruz, S. E. Moody, S. R. Master, J. L. Hartman, E. A. Keiper, M. B. Imielinski, et al. (2002). Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol. Endocrinol. 16:2034–2051.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas

    Orla M. Conneely, Biserka M. Jericevic & John P. Lydon

Authors
  1. Orla M. Conneely
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Biserka M. Jericevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John P. Lydon
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Conneely, O.M., Jericevic, B.M. & Lydon, J.P. Progesterone Receptors in Mammary Gland Development and Tumorigenesis. J Mammary Gland Biol Neoplasia 8, 205–214 (2003). https://doi.org/10.1023/A:1025952924864

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025952924864

Search

Navigation