Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53

Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. But the biologic mechanism of this inhibition remains to be determined. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis. Since p53 and bcl-2 genetically control the apoptotic process, we investigated whether or not these genes could be involved in the progesterone-induced apoptosis. We found a maximal 90 percent inhibition of cell proliferation with T47-D breast cancer cells after exposure to 10 microM progesterone for 72 hours. Control progesterone receptor negative MDA-231 cancer cells were unresponsive to these two concentrations of progesterone. After 24 hours of exposure to 10 microM progesterone, cytofluorometric analysis of T47-D breast cancer cells demonstrated 43 percent had undergone apoptosis without signs of necrosis. After 72 hours of exposure to 10 microM progesterone, 48 percent of the cells had undergone apoptosis and 40 percent demonstrated "leaky" membranes. Untreated cancer cells did not undergo apoptosis. Evidence proving apoptosis was also demonstrated by fragmentation of nuclear DNA into multiples of oligonucleosomal fragments. After 24 hours of exposure to either 1 microM or 10 microM progesterone, the expression by T47-D cancer cells of bcl-2 was down-regulated, and that of p53 was up-regulated as detected by semiquantitative RT-PCR analysis. These results demonstrate that progesterone at a concentration similar to that seen during the third trimester of pregnancy exhibited a strong antiproliferative effect on at least two breast cancer cell lines. Apoptosis was induced in the progesterone receptor expressing T47-D breast cancer cells.

This article has been cited by other articles:

				B. G. MOE, A. B. VEREIDE, A. ORBO, and G. SAGER High Concentrations of Progesterone and Mifepristone Mutually Reinforce Cell Cycle Retardation and Induction of Apoptosis Anticancer Res, April 1, 2009; 29(4): 1053 - 1058. [Abstract] [Full Text] [PDF]

				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]

				A. B. Spurdle, J. L. Hopper, X. Chen, M. R. E. McCredie, G. G. Giles, D. J. Venter, M. C. Southey, and G. Chenevix-Trench The Progesterone Receptor Exon 4 Val660Leu G/T Polymorphism and Risk of Breast Cancer in Australian Women Cancer Epidemiol. Biomarkers Prev., May 1, 2002; 11(5): 439 - 443. [Abstract] [Full Text] [PDF]

				J. D. Peck, B. S. Hulka, C. Poole, D. A. Savitz, D. Baird, and B. E. Richardson Steroid Hormone Levels during Pregnancy and Incidence of Maternal Breast Cancer Cancer Epidemiol. Biomarkers Prev., April 1, 2002; 11(4): 361 - 368. [Abstract] [Full Text] [PDF]

				G. C. Rodriguez, N. P. Nagarsheth, K. L. Lee, R. C. Bentley, D. K. Walmer, M. Cline, R. S. Whitaker, P. Isner, A. Berchuck, R. K. Dodge, et al. Progestin-Induced Apoptosis in the Macaque Ovarian Epithelium: Differential Regulation of Transforming Growth Factor-{beta} J Natl Cancer Inst, January 2, 2002; 94(1): 50 - 60. [Abstract] [Full Text] [PDF]

				J. E. Fata, V. Chaudhary, and R. Khokha Cellular Turnover in the Mammary Gland Is Correlated with Systemic Levels of Progesterone and Not 17{beta}-Estradiol During the Estrous Cycle Biol Reprod, September 1, 2001; 65(3): 680 - 688. [Abstract] [Full Text] [PDF]

				H.-Y. Li, S.-P. Chang, C.-C. Yuan, H.-T. Chao, H.-T. Ng, and Y.-J. Sung Nitric oxide induces extensive apoptosis in endometrial epithelial cells in the presence of progesterone: involvement of mitogen-activated protein kinase pathways Mol. Hum. Reprod., August 1, 2001; 7(8): 755 - 763. [Abstract] [Full Text] [PDF]

				M. J. Jayo, T. C. Register, C. L. Hughes, U. Blas-Machado, E. Sulistiawati, H. Borgerink, and C. S. Johnson Effects of an Oral Contraceptive Combination With or Without Androgen on Mammary Tissues: A Study in Rats Reproductive Sciences, July 1, 2000; 7(4): 257 - 265. [Abstract] [PDF]