This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Musgrove, E. A. Articles by Sutherland, R. L. Search for Related Content PubMed PubMed Citation Articles by Musgrove, E. A. Articles by Sutherland, R. L.

Antiprogestin Inhibition of Cell Cycle Progression in T-47D Breast Cancer Cells Is Accompanied by Induction of the Cyclin-Dependent Kinase Inhibitor p21

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

Progestin antagonists inhibit the proliferation of progesterone receptor-positive cells, including breast cancer cells, by G₁ phase-specific actions, but the molecular targets involved are not defined. Reduced phosphorylation of pRB, a substrate for G₁ cyclin-dependent kinases (CDKs) in vivo, was apparent after 9 h treatment of T-47D breast cancer cells with the antiprogestins RU 486 or ORG 31710, accompanying changes in S phase fraction. Although the abundance of cyclin D1, Cdk4, and Cdk6 did not decrease, cyclin D1-associated kinase activity was reduced by 50% at 9–18 h. Similarly, cyclin E-associated kinase activity decreased by 60% at 12–24 h in the absence of significant changes in the abundance of cyclin E and Cdk2. The CDK inhibitor p21 increased in mRNA and protein abundance and was present at increased levels in cyclin D1 and cyclin E complexes at times when their kinase activity was decreased. Increased p21 protein abundance was observed in another antiprogestin-sensitive cell line, BT 474, but not in two breast cancer cell lines insensitive to antiprogestins. These data suggest increased p21 abundance and concurrent inhibition of CDK activity as a mechanism for antiprogestin induction of growth arrest. Antiprogestin effects on proliferation were markedly reduced after ectopic expression of cyclin D1, indicating that inhibition of cyclin D1 function is a critical element in antiprogestin inhibition of proliferation. However, these data also implicate regulation of cyclin E function in antiprogestin regulation of cell cycle progression.

This article has been cited by other articles:

				A. Thakur, Y. Sun, A. Bollig, J. Wu, H. Biliran, S. Banerjee, F. H. Sarkar, and D. J. Liao Anti-invasive and Antimetastatic Activities of Ribosomal Protein S6 Kinase 4 in Breast Cancer Cells Clin. Cancer Res., July 15, 2008; 14(14): 4427 - 4436. [Abstract] [Full Text] [PDF]

				A. A. Goyeneche, R. W. Caron, and C. M. Telleria Mifepristone Inhibits Ovarian Cancer Cell Growth In vitro and In vivo Clin. Cancer Res., June 1, 2007; 13(11): 3370 - 3379. [Abstract] [Full Text] [PDF]

				R. Shao, K. Ljungstrom, B. Weijdegard, E. Egecioglu, J. Fernandez-Rodriguez, F.-P. Zhang, A. Thurin-Kjellberg, C. Bergh, and H. Billig Estrogen-induced upregulation of AR expression and enhancement of AR nuclear translocation in mouse fallopian tubes in vivo Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E604 - E614. [Abstract] [Full Text] [PDF]

				W. Chen, N. Ohara, J. Wang, Q. Xu, J. Liu, A. Morikawa, H. Sasaki, S. Yoshida, D. A. Demanno, K. Chwalisz, et al. A Novel Selective Progesterone Receptor Modulator Asoprisnil (J867) Inhibits Proliferation and Induces Apoptosis in Cultured Human Uterine Leiomyoma Cells in the Absence of Comparable Effects on Myometrial Cells J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1296 - 1304. [Abstract] [Full Text] [PDF]

				A. Skildum, E. Faivre, and C. A. Lange Progesterone Receptors Induce Cell Cycle Progression via Activation of Mitogen-Activated Protein Kinases Mol. Endocrinol., February 1, 2005; 19(2): 327 - 339. [Abstract] [Full Text] [PDF]

				Q. Xu, S. Takekida, N. Ohara, W. Chen, R. Sitruk-Ware, E. D. B. Johansson, and T. Maruo Progesterone Receptor Modulator CDB-2914 Down-Regulates Proliferative Cell Nuclear Antigen and Bcl-2 Protein Expression and Up-Regulates Caspase-3 and Poly(Adenosine 5'-Diphosphate-ribose) Polymerase Expression in Cultured Human Uterine Leiomyoma Cells J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 953 - 961. [Abstract] [Full Text] [PDF]

				E. A. Davison, C. S. L. Lee, M. J. Naylor, S. R. Oakes, R. L. Sutherland, L. Hennighausen, C. J. Ormandy, and E. A. Musgrove The Cyclin-Dependent Kinase Inhibitor p27 (Kip1) Regulates Both DNA Synthesis and Apoptosis in Mammary Epithelium But Is Not Required for Its Functional Development during Pregnancy Mol. Endocrinol., December 1, 2003; 17(12): 2436 - 2447. [Abstract] [Full Text] [PDF]

				J. K. Richer, B. M. Jacobsen, N. G. Manning, M. G. Abel, D. M. Wolf, and K. B. Horwitz Differential Gene Regulation by the Two Progesterone Receptor Isoforms in Human Breast Cancer Cells J. Biol. Chem., February 8, 2002; 277(7): 5209 - 5218. [Abstract] [Full Text] [PDF]

				R. G. Pestell, C. Albanese, A. T. Reutens, J. E. Segall, R. J. Lee, and A. Arnold The Cyclins and Cyclin-Dependent Kinase Inhibitors in Hormonal Regulation of Proliferation and Differentiation Endocr. Rev., August 1, 1999; 20(4): 501 - 534. [Abstract] [Full Text] [PDF]

				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]

				C. A. Lange, J. K. Richer, T. Shen, and K. B. Horwitz Convergence of Progesterone and Epidermal Growth Factor Signaling in Breast Cancer. POTENTIATION OF MITOGEN-ACTIVATED PROTEIN KINASE PATHWAYS J. Biol. Chem., November 20, 1998; 273(47): 31308 - 31316. [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. 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]

				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]

				C. M. Cover, S. J. Hsieh, S. H. Tran, G. Hallden, G. S. Kim, L. F. Bjeldanes, and G. L. Firestone Indole-3-carbinol Inhibits the Expression of Cyclin-dependent Kinase-6 and Induces a G1 Cell Cycle Arrest of Human Breast Cancer Cells Independent of Estrogen Receptor Signaling J. Biol. Chem., February 13, 1998; 273(7): 3838 - 3847. [Abstract] [Full Text] [PDF]

				H. H. Cha, E. J. Cram, E. C. Wang, A. J. Huang, H. G. Kasler, and G. L. Firestone Glucocorticoids Stimulate p21 Gene Expression by Targeting Multiple Transcriptional Elements within a Steroid Responsive Region of the p21waf1/cip1 Promoter in Rat Hepatoma Cells J. Biol. Chem., January 23, 1998; 273(4): 1998 - 2007. [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]