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Mechanisms of Resistance to Structurally Diverse Antiestrogens Differ under Premenopausal and Postmenopausal Conditions: Evidence from in Vitro Breast Cancer Cell Models

Department of Internal Medicine, University of Virginia Health Sciences System, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Richard J. Santen, University of Virginia, Department of Internal medicine, P.O. Box 801416, Charlottesville, Virginia 22908. E-mail: rjs5y{at}virginia.edu.

This study questioned whether the mechanisms of resistance to antiestrogens differ when acquired under premenopausal (Pre-M) vs. postmenopausal (PM) conditions and whether structurally diverse antiestrogens induce adaptation of differing signaling pathways. To address this issue, we conducted systematic studies under Pre-M vs. PM culture conditions with long-term exposure to different antiestrogens and examined the resultant "specific biologic signatures" of the various resistant cells. Estradiol stimulated growth and inhibited apoptosis of "pre-menopausal" antiestrogen-resistant cells but exerted opposite effects on their "post-menopausal" counterparts. Under Pre-M conditions, tamoxifen (TAM)-resistant cells exhibited a marked translocation of estrogen receptor from the nucleus into the cytoplasm, whereas this occurred to a lesser extent under PM conditions. MCF-7 cells exposed to PM but not Pre-M conditions exhibited up-regulation of basal epidermal growth factor (EGF) receptor (EGFR) levels, an effect exaggerated in cells exposed to 4-hydroxytamoxifen. Differing effects occurred in response to structurally divergent antiestrogens. Long-term treatment with both 4-hydroxytamoxifen and ICI182,780 increased EGFR levels, but this was not seen in response to TAM. Surprisingly, EGF administration slightly increased cell number in TAM-resistant cells, whereas only increasing cell weight and decreasing cell number in EGFR overexpressing-resistant cells. To assess potential differences among various parental cell lines, we induced resistance in cell lines obtained from other laboratories and confirmed the results from our own parental cells with minor differences. Together, these data demonstrate that culture of breast cancer cells under Pre-M and PM conditions and structurally diverse antiestrogens results in adaptive responses with differing biological signatures.