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.

公共卫生的相关性

即使在治疗目标核雌激素受体仍表示在乳腺癌可出现耐他莫昔芬。G蛋白偶联雌激素受体1(GPER1)在乳腺癌细胞他莫昔芬的作用介导的机制可以有助于他莫昔芬耐药性的发展。这项研究将显著增加的他莫昔芬的作用GPER1介导机制的认识,并提供了理解这一常用的乳腺癌治疗新模式。

机构
美国国立卫生研究院(NIH)
研究所
国家普通医学科学研究所
类型
研究精进奖(SC1)
项目#
5 sc1gm127175-02
应用#
9843681
研究部门
特别强调面板(ZGM1)
项目官员
Krasnova, Irina N
项目开始
2019-01-01
项目结束
2022-12-31
预算开始
2020-01-01
预算结束
2020-12-31
支持一年
2
财政年度
2020
总成本
间接成本
的名字
拉斯克鲁塞斯新墨西哥州立大学
部门
化学
类型
艺术和科学学院
兔褐#
173851965
城市
拉斯克鲁塞斯
状态
纳米
国家
美国
邮政编码
88003