TAMOXIFEN-RESISTANT FIBROBLAST GROWTH FACTOR-TRANSFECTED MCF-7 CELLS ARE CROSS-RESISTANT IN-VIVO TO THE ANTIESTROGEN ICI-182,780 AND 2 AROMATASE INHIBITORS

Although the antiestrogen tamoxifen has been the mainstay of therapy f or estrogen receptor (ER)-positive breast cancer, successful treatment of responsive tumors is often followed by the acquisition of tamoxife n resistance, Subsequently, only 30-40% of patients have a positive re sponse to second hormonal therapies, This lack of response might be ex plained by mechanisms for tamoxifen resistance that sensitize ER pathw ays to small amounts of estrogenic activity present in tamoxifen or th at bypass ER pathways completely, To elucidate one possible mechanism of tamoxifen resistance, we treated ovariectomized tumor-bearing mice injected with fibroblast growth factor (FGF)-transfected MCF-7 breast carcinoma cells with the steroidal antiestrogen ICI 182,780 or one of two aromatase inhibitors, 4-OHA or letrozole, These treatments did not slow estrogen-independent growth or prevent metastasis of tumors prod uced by FGF-transfected MCF-7 cells in ovariectomized nude mice, FGF-t ransfected cells had diminished responses to ICI 182,780 in vitro, sug gesting that autocrine activity of the transfected FGF may be replacin g estrogen as a mitogenic stimulus for tumor growth. ER levels in FGF transfectants were not down-regulated, and basal levels of transcripts for estrogen-induced genes or of ER-mediated transcription of estroge n response element (ERE) luciferase reporter constructs in the FGF exp ressing cells were not higher than parental cells, implying that alter ed hormonal responses are not due to down-regulation of ER or to FGF-m ediated activation of ER, These studies indicate that estrogen indepen dence may be achieved through FGF signaling pathways independent of ER pathways, If so, therapies directed at the operative mechanism might produce a therapeutic response or allow a response to a second course of antiestrogen treatment.