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Activation of the MAPK Pathway Enhances Sensitivity of MCF-7 Breast Cancer Cells to the Mitogenic Effect of Estradiol

Department of Internal Medicine (W.Y., J.-P.W., Y.L., R.J.S.) and Division of Biostatistics and Epidemiology (M.C.), University of Virginia, Charlottesville, Virginia 22908; and Department of Surgery (S.M.), Tokyo Dental College, Ichikawa City, Chiba 272, Japan

Address all correspondence and requests for reprints to: Wei Yue, Department of Internal Medicine, P.O. Box 801416, University of Virginia, Charlottesville, Virginia 22903. E-mail: wy9c{at}virginia.edu.

Long-term estrogen deprivation causes human breast cancer cells to develop hypersensitivity to the mitogenic effect of estradiol (E₂). Our prior studies demonstrated an association between enhanced MAPK activation and hypersensitivity in long-term estrogen-deprived (LTED) MCF-7 cells. Herein, we report that MAPK is constitutively activated in LTED cells and not dependent on serum factors. Additionally, activated MAPK levels fall upon reversion of the hypersensitivity. Importantly, we now provide direct evidence that enhanced MAPK causes hypersensitivity to E₂. We activated MAPK in wild-type MCF-7 cells using TGF, and demonstrated a 2–3 log enhancement of sensitivity to E₂. PD98059 abrogated the TGF-induced effect, indicating that MAPK activation is responsible for E₂ hypersensitivity. To determine the level at which MAPK activation enhanced E₂ sensitivity, we examined the dose-response effects of E₂ on several transcriptional readouts, including ERE-reporter activity and the levels of progesterone receptor and pS2. Wild-type and LTED cells exhibited nearly identical responses to E₂, suggesting that mechanisms downstream of estrogen receptor-mediated transcription are involved in inducing hypersensitivity. In support of this possibility, LTED and TGF-treated wild-type cells were hypersensitive to the effects of E₂ on the key cell cycle regulator, E2F1.

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