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Programmed Cell Death in an Estrogen-independent Human Breast Cancer Cell Line, MDA-MB-468¹

The Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

Previous studies have demonstrated that estrogen-responsive human breast cancer cells can be induced to undergo an energy-dependent, genetically programmed series of biochemical changes that result in the active suicide of the cells following estrogen ablation. In contrast, estrogen-independent human breast cancer cells do not activate this programmed cell death pathway following estrogen ablation. This could be due either to the absence of the cellular machinery required for programmed cell death or simply to the inability of estrogen ablation to activate this machinery. To discriminate between these two possibilities, the MDA-MB-468 estrogen-independent human mammary adenocarcinoma cell line was used as a model system to study the mechanism of cell death following cytotoxic drug treatment. Exposure of these cells to the fluorinated pyrimidines, 5-fluoro-2'-deoxyuridine or trifluorothymidine, resulted in growth inhibition and loss of proliferative capacity within 24 h. These changes occurred while cell membrane integrity was intact as measured by either cellular morphology or trypan blue exclusion. After 48 h of drug treatment, loss of cell membrane integrity was followed by cell lysis and a rapid decline in cell number. The addition of 16 µM thymidine prior to drug treatment prevented cell death, but thymidine did not rescue these cells once drug treatment was initiated. Analysis of DNA revealed the characteristic fragmentation into nucleosomal oligomers that is a hallmark of programmed cell death. Associated with this death pathway was a 15-fold induction of transforming growth factor ß₁ gene expression that has been previously observed in a variety of cellular systems undergoing programmed cell death. These results indicate that MDA-MB-468 estrogen-independent human mammary carcinoma cells retain the ability to undergo programmed cell death after treatment with cytotoxic drugs that induce a "thymineless" state.

¹ These research studies were supported by NIH Grants CA 49634 (N. E. D.) and CA 50601 (J. T. I.), and the Phil N. Allen Charitable Trust. D. K. A. was the recipient of a Susan G. Komen Foundation Fellowship. N. E. D. was the recipient of American Cancer Society Clinical Oncology Career Development Award 90–128 and a Merck Clinician Scientist Award from the Johns Hopkins University School of Medicine.

² To whom requests for reprints should be addressed, at Department of Pharmacology, University of Tennessee College of Medicine, 874 Union Avenue, Memphis, TN 38163.

Received 11/18/91. Accepted 4/ 3/92.

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