© 2003 by Oxford University Press
© 2003 Oxford University Press
ARTICLE |
Apoptotic Action of 17
-Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo
Affiliations of authors: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL (HL, CG, STP, BC, CO, JL, KM, ADLR, LW, VCJ); National Cancer Center, Goyang, Gyeonggi, Korea (ESL).
Correspondence to: V. Craig Jordan, OBE, PhD, DSc, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 8258 Olson, 303 E. Chicago Ave., Chicago, IL 60611 (e-mail: vcjordan{at}northwestern.edu).
Background: Resistance to tamoxifen, a selective estrogen receptor modulator (SERM), involves changes that prevent apoptosis and enhance cell proliferation and survival. Paradoxically, estrogen treatment inhibits the growth of long-term tamoxifen-treated breast tumors. Because of the increasing use of raloxifene, another SERM, to prevent osteoporosis and potentially reduce breast cancer risk, some women will develop raloxifene-resistant breast cancer. We developed a raloxifene-resistant MCF-7 cell model (MCF-7/Ral) and investigated the nature of raloxifene-resistant breast cancer and its response to estradiol. Methods: Raloxifene resistance and hormone responsiveness were assessed by proliferation assays and cell cycle analysis in parental MCF-7 and MCF-7/Ral cells. Nuclear factor 
B (NF-B) activity was investigated with a transient transfection assay. Apoptosis was investigated by annexin V staining, mRNA was measured by real-time polymerase chain reaction, and protein was measured by western blotting. Tumorigenesis was studied by injecting MCF-7 or MCF-7/Ral cells into ovariectomized athymic mice (10 per group) and monitoring tumor size weekly. All statistical tests were two-sided. Results: Basal NF-B activity was higher in MCF-7/Ral cells (1.6 U, 95% confidence interval [CI] = 1.2 to 2.0 U) than in MCF-7 cells (0.8 U, 95% CI = 0.4 to 1.1 U; P = .004). When cultured with 1 µM raloxifene, MCF-7/Ral cells grew statistically significantly (P<.001) faster than MCF-7 cells. Estradiol treatment of MCF-7/Ral cells arrested cells in G2/M phase of the cell cycle, decreased NF-B activity (0.2 U, 95% CI = 0.2 to 0.3 U; P<.001), increased expression of Fas protein and mRNA (4.5-fold, 95% CI = 2.8- to 6.3-fold versus 0.5-fold, 95% CI = 0.3- to 0.8-fold for control treatment; P<.001), and induced apoptosis. Treatment with either raloxifene or tamoxifen stimulated MCF-7/Ral tumor growth, suggesting that such tumors were resistant to both drugs. When a 9-week raloxifene or tamoxifen treatment was followed by a 5-week estradiol treatment, estradiol statistically significantly reduced the size of tumors stimulated by raloxifene or tamoxifen (at week 14, P = .004 for raloxifene and P<.001 for tamoxifen). Conclusions: Growth of raloxifene-resistant MCF-7/Ral cells in vitro and in vivo is repressed by estradiol treatment by a mechanism involving G2/M-phase arrest, decreased NF-B activity, and increased Fas expression to induce apoptosis.
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- Playing the Old Piano: Another Tune for Endocrine Therapy?
- Daniel F. Hayes
J Natl Cancer Inst 2003 95: 1565-1567.[Extract] [Full Text] [PDF]
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