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University of Colorado Health Sciences Center, Departments of Medicine and Pathology (G.I.O., C.A.L., K.B.H.), Department of Biochemistry, Biophysics and Genetics (I.E.S., R.A.S.), Department of Pharmacology (M.C.T., T.A.L.), The Molecular Biology Program (S.D.G., B.G., T.A.L., R.A.S., K.B.H.), Denver, Colorado 80262
Depending on the tissue, progesterone is classified as a proliferative or a differentiative hormone. To explain this paradox, and to simplify analysis of its effects, we used a breast cancer cell line (T47D-YB) that constitutively expresses the B isoform of progesterone receptors. These cells are resistant to the proliferative effects of epidermal growth factor (EGF). Progesterone treatment accelerates T47D-YB cells through the first mitotic cell cycle, but arrests them in late G1 of the second cycle. This arrest is accompanied by decreased levels of cyclins D1, D3, and E, disappearance of cyclins A and B, and sequential induction of the cyclin-dependent kinase (cdk) inhibitors p21 and p27Kip1. The retinoblastoma protein is hypophosphorylated and extensively down-regulated. The activity of the cell cycle-dependent protein kinase, cdk2, is regulated biphasically by progesterone: it increases initially, then decreases. This is consistent with the biphasic proliferative increase followed by arrest produced by one pulse of progesterone. A second treatment with progesterone cannot restart proliferation despite adequate levels of transcriptionally competent PR. Instead, a second progesterone dose delays the fall of p21 and enhances the rise of p27Kip1, thereby intensifying the progesterone resistance in an autoinhibitory loop. However, during the progesterone-induced arrest, the cell cycling machinery is poised to restart. The first dose of progesterone increases the levels of EGF receptors and transiently sensitizes the cells to the proliferative effects of EGF. We conclude that progesterone is neither inherently proliferative nor antiproliferative, but that it is capable of stimulating or inhibiting cell growth depending on whether treatment is transient or continuous. We also suggest that the G1 arrest after progesterone treatment is accompanied by cellular changes that permit other, possibly tissue-specific, factors to influence the final proliferative or differentiative state.
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A. Fritah, C. Saucier, J. Mester, G. Redeuilh, and M. Sabbah p21WAF1/CIP1 Selectively Controls the Transcriptional Activity of Estrogen Receptor {alpha} Mol. Cell. Biol., March 15, 2005; 25(6): 2419 - 2430. [Abstract] [Full Text] [PDF]
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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]
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 S. Kato, M. Pinto, A. Carvajal, N. Espinoza, C. Monso, A. Sadarangani, M. Villalon, J. J. Brosens, J. O. White, J. K. Richer, et al. Progesterone Increases Tissue Factor Gene Expression, Procoagulant Activity, and Invasion in the Breast Cancer Cell Line ZR-75-1 J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 1181 - 1188. [Abstract] [Full Text] [PDF]
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P. Zhang, J. H. Ostrander, E. J. Faivre, A. Olsen, D. Fitzsimmons, and C. A. Lange Regulated Association of Protein Kinase B/Akt with Breast Tumor Kinase J. Biol. Chem., January 21, 2005; 280(3): 1982 - 1991. [Abstract] [Full Text] [PDF]
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L. K. Pierson-Mullany and C. A. Lange Phosphorylation of Progesterone Receptor Serine 400 Mediates Ligand-Independent Transcriptional Activity in Response to Activation of Cyclin-Dependent Protein Kinase 2 Mol. Cell. Biol., December 15, 2004; 24(24): 10542 - 10557. [Abstract] [Full Text] [PDF]
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J. Botos, W. Xian, D. F. Smith, and C. L. Smith Progesterone Receptor Deficient in Chromatin Binding Has an Altered Cellular State J. Biol. Chem., April 9, 2004; 279(15): 15231 - 15239. [Abstract] [Full Text] [PDF]
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C. A. Lange Making Sense of Cross-Talk between Steroid Hormone Receptors and Intracellular Signaling Pathways: Who Will Have the Last Word? Mol. Endocrinol., February 1, 2004; 18(2): 269 - 278. [Abstract] [Full Text] [PDF]
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 E. P. Tierney, S. Tulac, S.-T. J. Huang, and L. C. Giudice Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation Physiol Genomics, December 16, 2003; 16(1): 47 - 66. [Abstract] [Full Text] [PDF]
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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]
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 S. Kyo, M. Nakamura, T. Kiyono, Y. Maida, T. Kanaya, M. Tanaka, N. Yatabe, and M. Inoue Successful Immortalization of Endometrial Glandular Cells with Normal Structural and Functional Characteristics Am. J. Pathol., December 1, 2003; 163(6): 2259 - 2269. [Abstract] [Full Text]
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W.-S. Lee, C.-W. Liu, S.-H. Juan, Y.-C. Liang, P.-Y. Ho, and Y.-H. Lee Molecular Mechanism of Progesterone-Induced Antiproliferation in Rat Aortic Smooth Muscle Cells Endocrinology, July 1, 2003; 144(7): 2785 - 2790. [Abstract] [Full Text] [PDF]
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X. Cui, P. Zhang, W. Deng, S. Oesterreich, Y. Lu, G. B. Mills, and A. V. Lee Insulin-Like Growth Factor-I Inhibits Progesterone Receptor Expression in Breast Cancer Cells via the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway: Progesterone Receptor as a Potential Indicator of Growth Factor Activity in Breast Cancer Mol. Endocrinol., April 1, 2003; 17(4): 575 - 588. [Abstract] [Full Text] [PDF]
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 Y.-C. Chou, N. Uehara, J. R. Lowry, and G. Shyamala Mammary epithelial cells of PR-A transgenic mice exhibit distinct alterations in gene expression and growth potential associated with transformation Carcinogenesis, March 1, 2003; 24(3): 403 - 409. [Abstract] [Full Text] [PDF]
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L. Labriola, M. Salatino, C. J. Proietti, A. Pecci, O. A. Coso, A. R. Kornblihtt, E. H. Charreau, and P. V. Elizalde Heregulin Induces Transcriptional Activation of the Progesterone Receptor by a Mechanism That Requires Functional ErbB-2 and Mitogen-Activated Protein Kinase Activation in Breast Cancer Cells Mol. Cell. Biol., February 1, 2003; 23(3): 1095 - 1111. [Abstract] [Full Text]
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 Y. Wan and S. K. Nordeen Overlapping but Distinct Profiles of Gene Expression Elicited by Glucocorticoids and Progestins Recent Prog. Horm. Res., January 1, 2003; 58(1): 199 - 226. [Abstract] [Full Text] [PDF]
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T. M. Ahola, N. Alkio, T. Manninen, and T. Ylikomi Progestin and G Protein-Coupled Receptor 30 Inhibit Mitogen-Activated Protein Kinase Activity in MCF-7 Breast Cancer Cells Endocrinology, December 1, 2002; 143(12): 4620 - 4626. [Abstract] [Full Text] [PDF]
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T. M. Ahola, T. Manninen, N. Alkio, and T. Ylikomi G Protein-Coupled Receptor 30 Is Critical for a Progestin-Induced Growth Inhibition in MCF-7 Breast Cancer Cells Endocrinology, September 1, 2002; 143(9): 3376 - 3384. [Abstract] [Full Text] [PDF]
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Y. Wan and S. K. Nordeen Overlapping but Distinct Gene Regulation Profiles by Glucocorticoids and Progestins in Human Breast Cancer Cells Mol. Endocrinol., June 1, 2002; 16(6): 1204 - 1214. [Abstract] [Full Text] [PDF]
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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]
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B. L. Powell, I. L. van Staveren, P. Roosken, F. Grieu, E. M.J.J. Berns, and B. Iacopetta Associations between common polymorphisms in TP53 and p21WAF1/Cip1 and phenotypic features of breast cancer Carcinogenesis, February 1, 2002; 23(2): 311 - 315. [Abstract] [Full Text] [PDF]
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E. A. Musgrove, L.-J. K. Hunter, C. S. L. Lee, A. Swarbrick, R. Hui, and R. L. Sutherland Cyclin D1 Overexpression Induces Progestin Resistance in T-47D Breast Cancer Cells Despite p27Kip1 Association with Cyclin E-Cdk2 J. Biol. Chem., December 7, 2001; 276(50): 47675 - 47683. [Abstract] [Full Text] [PDF]
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T. Shen, K. B. Horwitz, and C. A. Lange Transcriptional Hyperactivity of Human Progesterone Receptors Is Coupled to Their Ligand-Dependent Down-Regulation by Mitogen-Activated Protein Kinase-Dependent Phosphorylation of Serine 294 Mol. Cell. Biol., September 15, 2001; 21(18): 6122 - 6131. [Abstract] [Full Text] [PDF]
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 C. L. Chaffin, K. M. Schwinof, and R. L. Stouffer Gonadotropin and Steroid Control of Granulosa Cell Proliferation During the Periovulatory Interval in Rhesus Monkeys Biol Reprod, September 1, 2001; 65(3): 755 - 762. [Abstract] [Full Text] [PDF]
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 K. Webster, A. Taylor, and K. Gaston Oestrogen and progesterone increase the levels of apoptosis induced by the human papillomavirus type 16 E2 and E7 proteins J. Gen. Virol., January 1, 2001; 82(1): 201 - 213. [Abstract] [Full Text]
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Z. Wang, S. Kyo, M. Takakura, M. Tanaka, N. Yatabe, Y. Maida, M. Fujiwara, J. Hayakawa, M. Ohmichi, K. Koike, et al. Progesterone Regulates Human Telomerase Reverse Transcriptase Gene Expression via Activation of Mitogen-activated Protein Kinase Signaling Pathway Cancer Res., October 1, 2000; 60(19): 5376 - 5381. [Abstract] [Full Text]
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A. Swarbrick, C. S. L. Lee, R. L. Sutherland, and E. A. Musgrove Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells Mol. Cell. Biol., April 1, 2000; 20(7): 2581 - 2591. [Abstract] [Full Text]
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V. C.-L. Lin, E. H. Ng, S. E. Aw, M. G.-K. Tan, E. H.-L. Ng, and B. H. Bay Progesterone Induces Focal Adhesion in Breast Cancer Cells MDA-MB-231 Transfected with Progesterone Receptor Complementary DNA Mol. Endocrinol., March 1, 2000; 14(3): 348 - 358. [Abstract] [Full Text]
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J. P. Wiebe, D. Muzia, J. Hu, D. Szwajcer, S. A. Hill, and J. L. Seachrist The 4-Pregnene and 5{{alpha}}-Pregnane Progesterone Metabolites Formed in Nontumorous and Tumorous Breast Tissue Have Opposite Effects on Breast Cell Proliferation and Adhesion Cancer Res., February 1, 2000; 60(4): 936 - 943. [Abstract] [Full Text]
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M. K. R. Samuelsson, A. Pazirandeh, B. Davani, and S. Okret p57Kip2, a Glucocorticoid-Induced Inhibitor of Cell Cycle Progression in HeLa Cells Mol. Endocrinol., November 1, 1999; 13(11): 1811 - 1822. [Abstract] [Full Text]
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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]
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W. Tong and J. W. Pollard Progesterone Inhibits Estrogen-Induced Cyclin D1 and cdk4 Nuclear Translocation, Cyclin E- and Cyclin A-cdk2 Kinase Activation, and Cell Proliferation in Uterine Epithelial Cells in Mice Mol. Cell. Biol., March 1, 1999; 19(3): 2251 - 2264. [Abstract] [Full Text] [PDF]
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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]
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F. Vazquez, J. C. Rodriguez-Manzaneque, J. P. Lydon, D. P. Edwards, B. W. O'Malley, and M. L. Iruela-Arispe Progesterone Regulates Proliferation of Endothelial Cells J. Biol. Chem., January 22, 1999; 274(4): 2185 - 2192. [Abstract] [Full Text] [PDF]
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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]
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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]
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J. M. Kokontis, N. Hay, and S. Liao Progression of LNCaP Prostate Tumor Cells during Androgen Deprivation: Hormone-Independent Growth, Repression of Proliferation by Androgen, and Role for p27Kip1 in Androgen-Induced Cell Cycle Arrest Mol. Endocrinol., July 1, 1998; 12(7): 941 - 953. [Abstract] [Full Text]
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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]
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