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Long-term Treatment with Tamoxifen Facilitates Translocation of Estrogen Receptor out of the Nucleus and Enhances its Interaction with EGFR in MCF-7 Breast Cancer Cells

Department of Internal Medicine, University of Virginia Health Sciences System, Charlottesville, Virginia

Requests for reprints: Wei Yue, Department of Internal Medicine, University of Virginia, P.O. Box 801416, Charlottesville, VA 22908. Phone: 434-924-0399; Fax: 434-924-1284; E-mail: wy9c{at}virginia.edu.

The therapeutic benefit of tamoxifen in patients with hormone-dependent breast cancer is limited by acquired resistance to this drug. To investigate the biological alterations responsible for tamoxifen resistance, an in vitro model was established. After 6-month continuous exposure to tamoxifen (10^–7 mol/L), growth of MCF-7 breast cancer cells was no longer inhibited by this antiestrogen. Although there was no significant increase in the basal levels of activated mitogen-activated protein kinase (MAPK), tamoxifen-resistant (TAM-R) cells exhibited enhanced sensitivity to epidermal growth factor (EGF) and estradiol stimulated activation of MAPK. Tamoxifen elicited rapid phosphorylation of MAPK, in contrast to its antagonistic activity in control cells. Blockade of the EGF receptor (EGFR)/MAPK pathway caused more dramatic inhibition of growth of TAM-R cells than the control cells. An increased amount of estrogen receptor (ER) was coimmunoprecipitated with EGFR from TAM-R cells although the total levels of these receptors were not increased. Notably, ER seemed to redistribute to extranuclear sites in TAM-R cells. Increased ER immunoreactivity in the cytoplasm and plasma membrane of TAM-R cells was shown by fluorescent microscopy and by Western analysis of isolated cellular fractions. In TAM-R cells, an increased amount of c-Src was coprecipitated with EGFR or ER. Blockade of c-Src activity resulted in redistribution of ER back to the nucleus and in reduction of its interaction with EGFR. Prolonged blockade of c-Src activity restored sensitivity of TAM-R cells to tamoxifen. Our results suggest that enhanced nongenomic function of ER via cooperation with the EGFR pathway is one of the mechanisms responsible for acquired tamoxifen resistance. [Cancer Res 2007;67(3):1352–60]

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