Tamoxifen but Not 4-Hydroxytamoxifen Initiates Apoptosis in p53(−) Normal Human Mammary Epithelial Cells by Inducing Mitochondrial Depolarization

Despite the widespread clinical use of tamoxifen as a breast cancer prevention agent, the molecular mechanism of tamoxifen chemoprevention is poorly understood. Abnormal expression of p53 is felt to be an early event in mammary carcinogenesis. We developed an in vitro model of early breast cancer pr...

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Published in:	The Journal of biological chemistry Vol. 276; no. 7; pp. 5384 - 5394
Main Authors:	Dietze, Eric C., Caldwell, L. Elizabeth, Grupin, Svetlana L., Mancini, Mariangela, Seewaldt, Victoria L.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 16-02-2001 American Society for Biochemistry and Molecular Biology
Subjects:	Anticarcinogenic Agents - pharmacokinetics Anticarcinogenic Agents - pharmacology Apoptosis - drug effects Breast - cytology Breast - drug effects Caspases - metabolism Cell Culture Techniques - methods Cell Division - drug effects Cell Line Chromatography, High Pressure Liquid Epithelial Cells - cytology Epithelial Cells - drug effects Epithelial Cells - ultrastructure Estrogen Antagonists - pharmacokinetics Estrogen Antagonists - pharmacology Female Humans Membrane Potentials - drug effects Mitochondria - drug effects Mitochondria - physiology Mitochondria - ultrastructure Oncogene Proteins, Viral - genetics Repressor Proteins Tamoxifen - analogs & derivatives Tamoxifen - pharmacokinetics Tamoxifen - pharmacology Tumor Suppressor Protein p53 - physiology
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Summary:	Despite the widespread clinical use of tamoxifen as a breast cancer prevention agent, the molecular mechanism of tamoxifen chemoprevention is poorly understood. Abnormal expression of p53 is felt to be an early event in mammary carcinogenesis. We developed an in vitro model of early breast cancer prevention to investigate how tamoxifen and 4-hydroxytamoxifen may act in normal human mammary epithelial cells (HMECs) that have acutely lost p53 function. p53 function was suppressed by retrovirally mediated expression of the human papillomavirus type 16 E6 protein. Tamoxifen, but not 4-hydroxytamoxifen, rapidly induced apoptosis in p53(−) HMEC-E6 cells as evidenced by characteristic morphologic changes, annexin V binding, and DNA fragmentation. We observed that a decrease in mitochondrial membrane potential, mitochondrial condensation, and caspase activation preceded the morphologic appearance of apoptosis in tamoxifen-treated early passage p53(−) HMEC-E6 cells. p53(−) HMEC-E6 cells rapidly developed resistance to tamoxifen-mediated apoptosis within 10 passages in vitro. Resistance to tamoxifen in late passage p53(−) HMEC-E6 cells correlated with an increase in mitochondrial mass and a lack of mitochondrial depolarization and caspase activation following tamoxifen treatment. We hypothesize that an early event in the induction of apoptosis by tamoxifen involves mitochondrial depolarization and caspase activation, and this may be important for effective chemoprevention.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M007915200