© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 22, 1714-1723,
November 21, 2001
© 2001 Oxford University Press
ARTICLE |
Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17
-Estradiol
Affiliations of authors: R. X.-D. Song, R. A. McPherson, Z. Zhang, W. Yue, J. Wang, R. J. Santen, Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville; G. Mor, F. Naftolin, J. Song, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT.
Correspondence to: Richard J. Santen, M.D., Division of Endocrinology, University of Virginia Health Science Center, Charlottesville, VA 22908 (e-mail: rjs5y{at}virginia.edu).
Background: High doses of estrogen can promote tumor regression in postmenopausal women with hormone-dependent breast cancer, but the mechanism is unknown. We investigated the molecular basis of this process by using LTED cells, which were derived by growing MCF-7 breast cancer cells under long-term (6–24 months) estrogen-deprived conditions. Methods: We treated LTED and MCF-7 cells with various concentrations of 17
-estradiol (estradiol) and assayed their growth by counting the cells and measured apoptosis by annexin V staining and DNA fragmentation. Using western blot analysis, we also examined the expression of the apoptosis-inducing system of the Fas death receptor protein and its ligand, FasL, in these cells. To assess the involvement of Fas and FasL in the induction of apoptosis in LTED cells, we used activating anti-Fas antibodies and the universal caspase inhibitor Z-VAD. Finally, we examined the expression of Fas protein in E8CASS and BSK3 cells, two other cell lines derived by depriving MCF-7 cells of estrogen long term, and the responses of these cells to high-dose estradiol. All statistical tests were two-sided. Results: High concentrations of estradiol (
0.1 nM) resulted in a statistically significant, 60% reduction in the growth of LTED cells (P<.001) and in a sevenfold increase in apoptosis (P<.001) as compared with levels in vehicle-treated cells. Both LTED and MCF-7 cells expressed FasL, but only LTED cells expressed Fas. Treatment of LTED cells with 0.1 nM estradiol increased the expression of FasL. Activating anti-Fas antibodies increased apoptosis of LTED cells, which was further stimulated by estradiol. Z-VAD blocked estradiol-induced apoptosis. E8CASS cells, which express Fas protein, but not BSK3 cells, which do not, also responded to 0.1 nM estradiol by increasing apoptosis. Conclusion: Tumor regression induced by high-dose estrogen therapy in postmenopausal woman may result from estrogen activation of Fas-mediated apoptosis.
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