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Progestin Regulation of Cellular Proliferation^*

Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney New South Wales 2010, Australia

Correspondence: Address requests for reprints to: Dr. R. L. Sutherland, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, New South Wales, 2010 Australia.

Abstract

I. Introduction: THE control of cellular proliferation is known to involve a delicate balance between the effects of different regulatory molecules including hormones and growth factors which provide, in the immediate environment of the cell, signals to stimulate or inhibit cellular replication (1). The past decade has seen significant progress in the identification and characterization of novel regulatory molecules, generally referred to as growth factors, and definition of their molecular mechanisms of action (2, 3). With the recent emphasis on peptide growth factors it is perhaps less well appreciated that some of the largest physiological changes (both positive and negative) in rates of growth and cell proliferation are mediated by steroid hormones. Recent studies on breast cancer cells (4) and immature rat uterus (5, 6), illustrating estrogenic control of autocrine and paracrine growth factor production, support the view that some of these steroid-induced responses are intimately linked to growth factor-mediated pathways although debate continues as to whether the growth factor response is the cause, or the consequence, of the estrogenic effect on cellular proliferation (7, 8). Generally speaking, the molecular mechanisms by which steroid hormones control proliferation are not well defined, with the most developed knowledge being in the area of estrogen action where a number of recent reviews are available (4, 9–11).

Footnotes

^* The research in this laboratory is supported by the National Health and Medical Research Council (NHMRC) of Australia, the New South Wales State Cancer Council, MLC-Life Ltd, and the Government Employees Assistance to Medical Research Fund. Dr. Clarke is an MLC-Life Research Fellow; Dr Sutherland is an NHMRC Principal Research Fellow.

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				M. Nisolle, S. Gillerot, F. Casanas-Roux, J. Squifflet, M. Berliere, and J. Donnez Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy Hum. Reprod., November 1, 1999; 14(11): 2844 - 2850. [Abstract] [Full Text] [PDF]

				H. Wang, B. Masironi, H. Eriksson, and L. Sahlin A Comparative Study of Estrogen Receptors {alpha} and {beta} in the Rat Uterus Biol Reprod, October 1, 1999; 61(4): 955 - 964. [Abstract] [Full Text]

				H. A. Kester, C. Blanchetot, J. den Hertog, P. T. van der Saag, and B. van der Burg Transforming Growth Factor-beta -stimulated Clone-22 Is a Member of a Family of Leucine Zipper Proteins That Can Homo- and Heterodimerize and Has Transcriptional Repressor Activity J. Biol. Chem., September 24, 1999; 274(39): 27439 - 27447. [Abstract] [Full Text] [PDF]

				J. P. Lydon, G. Ge, F. S. Kittrell, D. Medina, and B. W. O'Malley Murine Mammary Gland Carcinogenesis Is Critically Dependent on Progesterone Receptor Function Cancer Res., September 1, 1999; 59(17): 4276 - 4284. [Abstract] [Full Text] [PDF]

				S. M.N. Hunt and C. L. Clarke Expression and Hormonal Regulation of the Sox4 Gene in Mouse Female Reproductive Tissues Biol Reprod, August 1, 1999; 61(2): 476 - 481. [Abstract] [Full Text]

				C. A. Lange, J. K. Richer, and K. B. Horwitz Hypothesis: Progesterone Primes Breast Cancer Cells for Cross-Talk with Proliferative or Antiproliferative Signals Mol. Endocrinol., June 1, 1999; 13(6): 829 - 836. [Full Text]

				H. Okada, M. Sanezumi, T. Nakajima, S. Okada, K. Yasuda, and H. Kanzaki Rapid down-regulation of CD63 transcription by progesterone in human endometrial stromal cells Mol. Hum. Reprod., June 1, 1999; 5(6): 554 - 558. [Abstract] [Full Text] [PDF]

				M. Dahmoun, K. Boman, S. Cajander, P. Westin, and T. Bäckström Apoptosis, Proliferation, and Sex Hormone Receptors in Superficial Parts of Human Endometrium at the End of the Secretory Phase J. Clin. Endocrinol. Metab., May 1, 1999; 84(5): 1737 - 1743. [Abstract] [Full Text]

				B. L. Wagner, G. Pollio, P. Giangrande, J. C. Webster, M. Breslin, D. E. Mais, C. E. Cook, W. V. Vedeckis, J. A. Cidlowski, and D. P. McDonnell The Novel Progesterone Receptor Antagonists RTI 3021-012 and RTI 3021-022 Exhibit Complex Glucocorticoid Receptor Antagonist Activities: Implications for the Development of Dissociated Antiprogestins Endocrinology, March 1, 1999; 140(3): 1449 - 1458. [Abstract] [Full Text]

				V. C-L. Lin, E. H. Ng, S. E. Aw, M. G-K. Tan, E. H-L. Ng, V. S-W. Chan, and G. H. Ho Progestins Inhibit the Growth of MDA-MB-231 Cells Transfected with Progesterone Receptor Complementary DNA Clin. Cancer Res., February 1, 1999; 5(2): 395 - 403. [Abstract] [Full Text] [PDF]

				J. K. Richer, C. A. Lange, N. G. Manning, G. Owen, R. Powell, and K. B. Horwitz Convergence of Progesterone with Growth Factor and Cytokine Signaling in Breast Cancer. PROGESTERONE RECEPTORS REGULATE SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION EXPRESSION AND ACTIVITY J. Biol. Chem., November 20, 1998; 273(47): 31317 - 31326. [Abstract] [Full Text] [PDF]

				T. Kurita, P. Young, J. R. Brody, J. P. Lydon, B. W. O'Malley, and G. R. Cunha Stromal Progesterone Receptors Mediate the Inhibitory Effects of Progesterone on Estrogen-Induced Uterine Epithelial Cell Deoxyribonucleic Acid Synthesis Endocrinology, November 1, 1998; 139(11): 4708 - 4713. [Abstract] [Full Text] [PDF]

				T. F. Ogle, P. George, and D. Dai Progesterone and Estrogen Regulation of Rat Decidual Cell Expression of Proliferating Cell Nuclear Antigen Biol Reprod, August 1, 1998; 59(2): 444 - 450. [Abstract] [Full Text]

				V. Rider, B. F. Kimler, and W. M. Justice Progesterone-Growth Factor Interactions in Uterine Stromal Cells Biol Reprod, July 1, 1998; 59(3): 464 - 469. [Full Text]

				M.-H. Jeng, C. Kao, L. Sivaraman, S. Krnacik, L. W. K. Chung, D. Medina, O. M. Conneely, and B. W. O'Malley Reconstitution of Estrogen-Dependent Transcriptional Activation of an Adenoviral Target Gene in Select Regions of the Rat Mammary Gland Endocrinology, June 1, 1998; 139(6): 2916 - 2925. [Abstract] [Full Text] [PDF]

				G. I. Owen, J. K. Richer, L. Tung, G. Takimoto, and K. B. Horwitz Progesterone Regulates Transcription of the p21WAF1 Cyclindependent Kinase Inhibitor Gene through Sp1 and CBP/p300 J. Biol. Chem., April 24, 1998; 273(17): 10696 - 10701. [Abstract] [Full Text] [PDF]

				E. A. Musgrove, A. Swarbrick, C. S. L. Lee, A. L. Cornish, and R. L. Sutherland Mechanisms of Cyclin-Dependent Kinase Inactivation by Progestins Mol. Cell. Biol., April 1, 1998; 18(4): 1812 - 1825. [Abstract] [Full Text]

				E. K. Gass, S. A. Leonhardt, S. K. Nordeen, and D. P. Edwards The Antagonists RU486 and ZK98299 Stimulate Progesterone Receptor Binding to Deoxyribonucleic Acid in Vitro and in Vivo, but Have Distinct Effects on Receptor Conformation Endocrinology, April 1, 1998; 139(4): 1905 - 1919. [Abstract] [Full Text] [PDF]

				C. Yeates, S. M. N. Hunt, R. L. Balleine, and C. L. Clarke Characterization of a Truncated Progesterone Receptor Protein in Breast Tumors J. Clin. Endocrinol. Metab., February 1, 1998; 83(2): 460 - 467. [Abstract] [Full Text]

				P. H. Giangrande, G. Pollio, and D. P. McDonnell 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., December 26, 1997; 272(52): 32889 - 32900. [Abstract] [Full Text] [PDF]

				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 Biphasic Regulation of Breast Cancer Cell Growth by Progesterone: Role of the Cyclin-Dependent Kinase Inhibitors, p21 and p27Kip1 Mol. Endocrinol., October 1, 1997; 11(11): 1593 - 1607. [Abstract] [Full Text]

				M. M. Miller, R. A. James, J. K. Richer, D. F. Gordon, W. M. Wood, and K. B. Horwitz Progesterone Regulated Expression of Flavin-Containing Monooxygenase 5 by the B-Isoform of Progesterone Receptors: Implications for Tamoxifen Carcinogenicity J. Clin. Endocrinol. Metab., September 1, 1997; 82(9): 2956 - 2961. [Abstract] [Full Text] [PDF]

				T. K. Said, O. M. Conneely, D. Medina, B. W. O'Malley, and J. P. Lydon Progesterone, in Addition to Estrogen, Induces Cyclin D1 Expression in the Murine Mammary Epithelial Cell, in Vivo Endocrinology, September 1, 1997; 138(9): 3933 - 3939. [Abstract] [Full Text] [PDF]

				J. D. Graham and C. L. Clarke Physiological Action of Progesterone in Target Tissues Endocr. Rev., August 1, 1997; 18(4): 502 - 519. [Abstract] [Full Text] [PDF]

				H. A. Kester, B.-j. M. van der Leede, P. T. van der Saag, and B. van der Burg Novel Progesterone Target Genes Identified by an Improved Differential Display Technique Suggest That Progestin-induced Growth Inhibition of Breast Cancer Cells Coincides with Enhancement of Differentiation J. Biol. Chem., June 27, 1997; 272(26): 16637 - 16643. [Abstract] [Full Text] [PDF]

				T. A. Jackson, J. K. Richer, D. L. Bain, G. S. Takimoto, L. Tung, and K. B. Horwitz The Partial Agonist Activity of Antagonist-Occupied Steroid Receptors Is Controlled by a Novel Hinge Domain-Binding Coactivator L7/SPA and the Corepressors N-CoR or SMRT Mol. Endocrinol., June 1, 1997; 11(6): 693 - 705. [Abstract] [Full Text]

				R. F. Casper, N. J. MacLusky, C. Vanin, and T. J. Brown Rationale for Estrogen With Interrupted Progestin as a New Low-Dose Hormonal Replacement Therapy Reproductive Sciences, September 1, 1996; 3(5): 225 - 234. [Abstract] [PDF]