大多数乳腺癌表达雌激素受体(ER?)并且是雌激素依赖性的。呃?-乳腺癌阳性，呃?拮抗剂会降低细胞增殖和肿瘤生长。他莫西芬(Tam)，急诊室?乳腺癌细胞的拮抗剂，是诊断为ER患者最广泛使用的辅助治疗吗?阳性的乳腺癌。虽然Tam治疗对大多数患者是有效的，但仍有部分患者存在先天性Tam耐药，长期治疗后出现Tam耐药仍是一个临床相关结果。Tam耐药的分子机制尚不清楚。而谭的行为通常完全归因于ER?在缺乏ER的乳腺癌细胞中已观察到Tam的拮抗作用。 suggesting alternative mechanisms of Tam action. We have shown that GPER1 mediates Tam action in breast cancer cells via induction of IGFBP-1 expression and subsequent inhibition of IGF-1R-dependent cell signaling. Additionally, our data indicate that this GPER1-mediated mechanism of Tam action inhibits IGF-1-stimulated ER? phosphorylation. The role of IGFBPs during Tam treatment and the development of Tam resistance has not been adequately studied. GPER1-mediated mechanisms of Tam action in breast cancer cells modulate IGF-1R activity and inhibit phosphorylation-dependent ER? signaling. To test this hypothesis, three independent Aims are proposed. Included in all three Aims are experiments utilizing a panel of breast cancer cell lines to model Tam efficacy in multiple breast cancer subtypes. Completion of these aims will result in (1) Defining the role of IGFBP family members during Tam treatment, (2) Elucidating GPER1-mediated mechanisms that inhibit phosphorylation-dependent ER? activity in Tam- treated breast cancer cells, and (3) Determine the IGFBP-dependent molecular mechanisms that drive Tam resistance via modulation of growth factor signaling. Upon completion of these Aims, our knowledge regarding the molecular mechanisms of GPER1-mediated Tam action in breast cancer cells will be significantly increased and the molecular mechanisms of the role of GPER1 during the development of Tam resistance will be more clearly defined. Data obtained from these experiments will provide new models of understanding Tam action for future animal model and clinical studies of this commonly used therapeutic.