Skip to main content
SpringerLink
Log in

Estrogen and Progestin Regulation of Cell Cycle Progression

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

Abstract

Estrogens and progesterone, acting via theirspecific nuclear receptors, are essential for normalmammary gland development and differentiated function.The molecular mechanisms through which these effects are mediated are not well defined, althoughsignificant recent progress has been made in linkingsteroid hormone action to cell cycle progression. Thisreview summarizes data identifying c-myc and cyclin D1 as major downstream targets of bothestrogenand progestin-stimulated cell cycle progressionin human breast cancer cells. Additionally, estrogeninduces the formation of high specific activity forms of the cyclin E-Cdk2 enzyme complex lacking thecyclin-dependent kinase (CDK)3 inhibitor, p21. Thedelayed growth inhibitory effects of progestins, whichare likely to be prerequisites for manifestation of their function in differentiation, alsoinvolve decreases in cyclin D1 and E gene expression andrecruitment of CDK inhibitors into cyclin D1-Cdk4 andcyclin E-Cdk2 complexes. Thus estrogens and progestins affect CDK function not only by effects oncyclin abundance but also by regulating the recruitmentof CDK inhibitors and, as yet undefined, additionalcomponents which determine the activity of the CDK complexes. These effects of estrogens andprogestins are likely to be major contributors to theirregulation of mammary epithelial cell proliferation anddifferentiation.

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.

Similar content being viewed by others

References

  1. S. Nandi, R. C. Guzman, and J. Yang (1995). Hormones and mammary carcinogenesis in mice, rats and humans: a unifying hypothesis. Proc. Natl. Acad. Sci. USA 92:3650-3657.

    Google Scholar 

  2. J. P. Lyndon, F. J. DeMayo, C. R. Funk, S. K. Mani, A. R. Hughes, C. A. Montgomery, G. Shyamala, O. M. Conneely, and B.W. O'Malley (1995). Mice lacking progesterone receptor exhibit pleiotrophic reproductive abnormalities. Genes Dev. 9:2266-2278.

    Google Scholar 

  3. K. S. Korach, J. F. Couse, S. W. Curtis, T. F. Washburn, J. Lindzey, K. S. Kimbro, E. M. Eddy, A. Miglaccio, S. M. Snedeker, D. B. Lubahn, D. W. Schomberg, and E. P. Smith (1996). Estrogen receptor gene disruption: molecular characterization and experimental and clinical phenotypes. Rec. Prog. Horm. Res. 51:159-186.

    Google Scholar 

  4. C. J. Ormandy, A. Camus, J. Barra, D. Damotte, B. Lucas, H. Buteau, M. Edery, N. Brousse, C. Babinet, N. Binart, and P. A. Kelly (1997). Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev. 11:167-178.

    Google Scholar 

  5. C. L. Clarke and R. L. Sutherland (1990). Progestin regulation of cellular proliferation. Endocrine. Rev. 11:266-302.

    Google Scholar 

  6. S. M. Shafie, and F. H. Grantham (1981). Role of hormones in the growth and regression of human breast cancer cells (MCF-7) transplanted into athymic nude mice. J. Natl. Cancer Inst. 67:51-56.

    Google Scholar 

  7. I. J. Laidlaw, R. B. Clarke, A. Howell, A. W. M. C. Owen, C. S. Potten, and E. Anderson (1995). The proliferation of normal human breast tissue implanted into athymic nude mice is stimu-lated by oestrogen but not progesterone. Endocrinology 136:164-171.

    Google Scholar 

  8. O. Pearson, D. West, V. Hollander, and N. Treves (1954). Evaluation of endocrine therapy for advanced breast cancer. J. Am. Med. Assoc. 154:234-239.

    Google Scholar 

  9. B. Henderson, R. Ross, and L. Bernstein (1988). Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation Award lecture. Cancer Res. 48:246-253.

    Google Scholar 

  10. M. E. Lippman, and G. Bolan (1975). Oestrogen-respon sive human breast cancer in long term tissue culture. Nature 256:592-593.

    Google Scholar 

  11. E. A. Musgrove, C. S. L. Lee, and R. L. Sutherland (1991). Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor a, epidermal growth factor receptor, c-fos and c-myc genes. Mol. Cell. Biol. 11:5032-5043.

    Google Scholar 

  12. S. D. Groshong, G. I. Owen, B. Grimison, I. E. Schauer, M. C. Todd, T. A. Langan, R. A. Sclafani, C. A. Lange, and K. B. Horwitz (1997). Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27Kip1. Mol. Endocrinol. 11:1593-1601.

    Google Scholar 

  13. R. L. Sutherland, R. R. Reddel, and M. D. Green (1983). Effects of oestrogens on cell proliferation and cell cycle kinetics. A hypothesis on the cell cycle effects of antioestrogens. Eur. J. Cancer Clin. Oncol. 19:307-318.

    Google Scholar 

  14. L. Martin, R. M. Das, and C. A. Finn (1973). The inhibition by progesterone of uterine epithelial proliferation in the mouse. J. Endocrinol. 57:549-554.

    Google Scholar 

  15. L. Martin, C. A. Finn, and G. Trinder (1973). DNA synthesis in the endometrium of progesterone-tre ated mice. J. Endocrinol. 56:303-307.

    Google Scholar 

  16. B. S. Leung, and A. H. Potter (1987). Mode of estrogen action on cell proliferation in CAMA-1 cells: II. Sensitivity of G1 phase population. J. Cell. Biochem. 34:213-225.

    Google Scholar 

  17. R. L. Sutherland, R. E. Hall, and I. W. Taylor (1983). Cell proliferation kinetics of MCF-7 human mammary carcinoma cells in culture and effects of tamoxifen on exponentially growing and plateau-phase cells. Cancer Res. 43:3998-4006.

    Google Scholar 

  18. C. K. Osborne, D. H. Boldt, G. M. Clark, and J. M. Trent (1983). Effects of tamoxifen on human breast cancer cell cycle kinetics: accumulation of cells in early G1 phase. Cancer Res. 43:3583-3585.

    Google Scholar 

  19. I. W. Taylor, P. J. Hodson, M. D. Green, and R. L. Sutherland (1983). Effects of tamoxifen on cell cycle progression of synchronous MCF-7 human mammary carcinoma cells. Cancer Res. 43:4007-4010.

    Google Scholar 

  20. R. R. Reddel, L. C. Murphy, and R. L. Sutherland (1984). Factors affecting the sensitivity of T-47D human breast cancer cells to tamoxifen. Cancer Res. 44:2398-2405.

    Google Scholar 

  21. B. van der Burg, G. R. Rutteman, M. A. Blankenstein, S. W. de Laat, and E. J. J. van Zoelen (1988). Mitogenic stimulation of human breast cancer cells in a growth factor-defined medium: synergistic action of insulin and estrogen. J. Cell. Physiol. 134:101-108.

    Google Scholar 

  22. J. S. Foster, and J. Wimalasena (1996). Estrogen regulated activity of cyclin dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells. Mol. Endocrinol. 10:488-498.

    Google Scholar 

  23. L. Altucci, R. Addeo, L. Cicatiello, S. Davois, M. G. Parker, M. Truss, M. Beato, V. Sica, F. Bresciani, and A. Weisz (1996). 17β-estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105RB phosphorylation during mitogenic stimulation of G1-arrested human breast cancer cells. Oncogene 12:2315-2324.

    Google Scholar 

  24. O. W. J. Prall, B. Sarcevic, E. A. Musgrove, C. K. W. Watts, and R. L. Sutherland (1997). Estrogen-induce d activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J. Biol. Chem. 272:10882-10894.

    Google Scholar 

  25. M. D. Planas-Silva, and R. A. Weinberg (1997). Estrogen-dependent cyclin E-cdk2 activation through p21 redistribution. Mol. Cell. Biol. 17:4059-4069.

    Google Scholar 

  26. R. L. Sutherland, R. E. Hall, G. Y. N. Pang, E. A. Musgrove, and C. L. Clarke (1988). Effect of medroxyprogeste rone acetate on proliferation and cell cycle kinetics of human mammary carcinoma cells. Cancer Res. 48:5084-5091.

    Google Scholar 

  27. E. A. Musgrove, J. A. Hamilton, C. S. L. Lee, K. J. E. Sweeney, C. K. W. Watts, and R. L. Sutherland (1993). Growth factor, steroid and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. Mol. Cell. Biol. 13:3577-3587.

    Google Scholar 

  28. E. A. Musgrove, A. Swarbrick, C. S. L. Lee, A. L. Cornish, and R. L. Sutherland (1998). Mechanisms of CDK inactivation by progestins. (submitted).

  29. E. Kalkhoven, L. Kwakkenbos-Isbrücker, C. L. Mummery, S. W. de Laat, A. J.M. van den Eijnen-van Raij, P. T. van der Saag, and B. van der Burg (1995). The role of TGF-β production in growth inhibition of breast-tumor cells by progestins. Int. J. Cancer 61:80-86.

    Google Scholar 

  30. E. A. Musgrove and R. L. Sutherland (1994). Cell cycle control by steroid hormones. Seminars in Cancer Biol. 5:381-389.

    Google Scholar 

  31. C. J. Sherr (1994). G1 phase progression: cycling on cue. Cell 79:551-555.

    Google Scholar 

  32. D. O. Morgan (1995). Principles of CDK regulation. Nature 374:131-134.

    Google Scholar 

  33. D. O. Morgan (1996). The dynamics of cyclin dependent kinase structure. Curr. Opin. Cell Biol. 8:767-772.

    Google Scholar 

  34. C. J. Sherr and J. M. Roberts (1995). Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 9:1149-1163.

    Google Scholar 

  35. H. Hirai, M. F. Roussel, J.-Y. Kato, R. A. Ashmun, and C. J. Sherr (1995). Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol. Cell. Biol. 15:2672-2681.

    Google Scholar 

  36. I. Reynisdøttir, and J. Massague (1997). The subcellular loca-tions of p15Ink4b and p27Kip1 coordinate their inhibitory interac-tions with cdk4 and cdk2. Genes Dev. 11:492-503.

    Google Scholar 

  37. A. A. Russo, P. D. Jeffrey, A. K. Patten, J. Massague, and N. Pavletich (1996). Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 com-plex. Nature 382:325-331.

    Google Scholar 

  38. H. Zhang, G. J. Hannon, and D. Beach (1994). p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 8:1750-1758.

    Google Scholar 

  39. T. J. Soos, H. Kiyokawa, J. S. Yan, M. S. Rubin, A. Giordano, A. DeBlasio, S. Bottega, B. Wong, J. Mendelsohn, and A. Koff (1996). Formation of p27-CDK complexes during the human mitotic cell cycle. Cell Growth Differ. 7:135-146.

    Google Scholar 

  40. J. LaBauer, M. D. Garrett, L. F. Stevenson, J. M. Slingerland, C. Sandhu, H. S. Chou, A. Fattaey, and E. Harlow (1997). New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11:847-862.

    Google Scholar 

  41. M. Henriksson and B. Lüscher (1996). Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv. Cancer Res. 68:109-182.

    Google Scholar 

  42. H. Hermeking, J. O. Funk, M. Reichert, J. W. Ellwart, and D. Eick (1995). Abrogation of p53-induced cell cycle arrest by c-Myc: evidence for an inhibitor of p21WAF1/CIP1/SDI1. Oncogene 11:1409-1415.

    Google Scholar 

  43. J. Vlach, S. Hennecke, K. Alevizopoulos, D. Conti, and B. Amati (1996). Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. EMBO J. 15:6595-6604.

    Google Scholar 

  44. K. Galaktionov, X. Chen, and D. Beach (1996). Cdc25 cell-cycle phosphatase as a target of c-myc. Nature 382:511-517.

    Google Scholar 

  45. A. Weisz and F. Bresciani (1988). Estrogen induces expression of c-fos and c-myc protooncogenes in rat uterus. Mol. Endocrinol. 2:816-824.

    Google Scholar 

  46. L. J. Murphy, L. C. Murphy, and H. G. Friesen (1987). Estrogen induction of N-myc and c-myc proto-oncogene expression in the rat uterus. Endocrinology 120:1882-1888.

    Google Scholar 

  47. D. Dubik, T. C. Dembinski, and R. P. C. Shiu (1987). Stimulation of c-myc oncogene expression associated with estrogen-induced proliferation of human breast cancer cells. Cancer Res. 47:6517-6521.

    Google Scholar 

  48. E. Leygue, R. Gol-Winkler, A. Gompel, C. Louis-Sylvestre, L. Soquet, S. Staub, F. Kuttenn, and P. Mauvais-Jarvis (1995). Estradiol stimulates c-myc protooncogene expression in normal human breast epithelial cells in culture. J. Steroid Biochem. Mol. Biol. 52:299-305.

    Google Scholar 

  49. D. Dubik and R. P. C. Shiu (1992). Mechanism of estrogen activation of c-myc oncogene expression. Oncogene 7:1587-1594.

    Google Scholar 

  50. P. H. Watson, R. T. Pon, and R. P. C. Shiu (1991). Inhibition of c-myc expression by phosphorothioate antisense oligonucle-otide identifies a critical role for c-myc in the growth of human breast cancer. Cancer Res. 51:3996-4000.

    Google Scholar 

  51. C. K. W. Watts, A. Brady, B. Sarcevic, A. deFazio, E. A. Musgrove, and R. L. Sutherland (1995). Antiestrogen inhibition of cell cycle progression in breast cancer cells is associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation. Mol. Endocrinol. 9:1804-1813.

    Google Scholar 

  52. L. Zhu, E. Harlow, and B. D. Dynlacht (1995). p107 uses a p21 CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev. 9:1740-1752.

    Google Scholar 

  53. P. Shiyanov, S. Bagchi, G. Adami, J. Kokontis, N. Hay, M. Arroyo, A. Morozov, and P. Raychaudhuri (1996). p21 disrupts the interaction between cdk2 and the E2F-p130 complex. Mol. Cell. Biol. 16:737-744.

    Google Scholar 

  54. R. L. Sutherland, C. S. L. Lee, A. L. Cornish, and E. A. Musgrove (1995). Progestin regulation of cell proliferation in the breast and endometrium. In D. T. Baird, G. Schütz, and R. Krattenmacher (eds.), Organ-Selective Actions of Steroid Hormones, Springer, Berlin, pp. 85-105.

    Google Scholar 

  55. E. A. Musgrove, C. S. L. Lee, M. F. Buckley, and R. L. Sutherland (1994). Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc. Natl. Acad. Sci. USA 91:8022-8026.

    Google Scholar 

  56. E. A. Musgrove, B. Sarcevic, and R. L. Sutherland (1996). Inducible expression of cyclin D1 in T-47D human breast can-cer cells is sufficient for CDK2 activation and pRB hyperpho-sphorylation. J. Cell Biochem. 60:362-377.

    Google Scholar 

  57. T. C. Wang, R.D. Cardiff, L. Zukerberg, E. Lees, A. Arnold, and E. V. Schmidt (1994). Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:669-671.

    Google Scholar 

  58. P. Sicinski, J. Liu Donaher, S. B. Parker, T. Li, A. Fazeli, H. Gardner, S. Z. Haslam, R. B. Bronson, S. J. Elledge, and R. A. Weinberg (1995). Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621-630.

    Google Scholar 

  59. V. Fantl, G. Stamp, A. Andrews, I. Rosewell, and C. Dickson (1995). Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 9:2364-2372.

    Google Scholar 

  60. M. S. J. Wong and L. C. Murphy (1991). Differential regulation of c-myc by progestins and antiestrogens in T-47D human breast cancer cells. J. Steroid Biochem. Mol. Biol. 39:39-44.

    Google Scholar 

  61. J. Lukas, J. Bartkova, and J. Bartek (1996). Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-depend ent kinase-pRb-cont rolled G1 checkpoint. Mol. Cell. Biol. 16:6917-6925.

    Google Scholar 

Download references

Authors
  1. Robert L. Sutherland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Owen W. J. Prall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Colin K. W. Watts
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elizabeth A. Musgrove
    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

Sutherland, R.L., Prall, O.W.J., Watts, C.K.W. et al. Estrogen and Progestin Regulation of Cell Cycle Progression. J Mammary Gland Biol Neoplasia 3, 63–72 (1998). https://doi.org/10.1023/A:1018774302092

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018774302092

Search

Navigation