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O'Regan RM , Osipo C , Ariazi E , Lee ES , Meeke K , Morris C , Bertucci A , Sarker MAB , Grigg R , Jordan VC
Development and therapeutic options for the treatment of raloxifene-stimulated breast cancer in athymic mice
CLINICAL CANCER RESEARCH. 2006 Part;12(7) :2255-2263
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Purpose: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research is focused on crosstalk between growth factor receptors and the estrogen receptor alpha (ER alpha) pathway. There is increasing clinical use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment of breast cancer in raloxifene-exposed women. Experimental Design: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance. Results: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17 beta-estradiol. Epidermal growth factor receptor/HER1 and HER2/neu mRNAs were increased in MCF-7RALT tumors. The HER2/neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT tumors in vivo. Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/neu, total HER2/neu, phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly, ER alpha protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant completely inhibited the growth and ER alpha activity of MCF-7RALT tumors. The coactivator of ER alpha, amplified in breast cancer-1! protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity of ER alpha in cells derived from the MCF-7RALT tumors. Conclusions: These results suggest that overexpression and increased activity of HER2/neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression of basal activity of ER alpha could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only fulvestrant blocked growth and ER alpha activity.