Mechanism of Aromatase Inhibitor Resistance

描述（由申请人提供）：临床试验强调了芳香酶抑制剂在乳腺癌治疗中的重要性。然而，与所有长期药物治疗一样，耐药性确实通过目前未知的机制发展。该实验室假设，对芳香酶抑制剂的抗性确实需要一种替代信号通路，使细胞能够适应抑制剂的存在，但仍然进行正常的细胞增殖。为了解决这个问题，该实验室已经产生了MCF-7aro（芳香酶过表达）乳腺癌细胞系，这些细胞系对芳香酶抑制剂和抗雌激素他莫昔芬具有抗性。1.为了研究与芳香化酶抑制剂耐药相关的候选基因，本实验室打算对MCF-7aro耐药细胞系进行微阵列分析。2.为了更好地了解微阵列鉴定的基因如何参与芳香化酶抑制剂的抗性，将通过细胞培养中的基因过表达或敲低以及激活的信号转导通路的分析来进行进一步的机制研究。该项目具有重要的临床意义，因为乳腺癌的有效治疗确实依赖于在分子水平上了解耐药性。

DESCRIPTION (provided by applicant): Clinical trials have highlighted the importance of aromatase inhibitors in the treatment of breast cancer. Yet, as with all prolonged drug therapy, resistance does develop via a currently unknown mechanism. This lab hypothesizes that resistance to aromatase inhibitors does entail an alternate signaling pathway that allows cells to adapt to the presence of the inhibitor, but still undergo normal cell proliferation. To address this question, this lab has generated MCF-7aro (aromatase overexpressed) breast cancer cell lines that are resistant to aromatase inhibitors and the anti-estrogen tamoxifen. 1. To investigate candidate genes involved in resistance to aromatase inhibitors, this lab intends to perform microarray analysis of the MCF-7aro resistant cell lines. 2. To better understand how genes identified by microarray are involved in resistance to aromatase inhibitors, further mechanistic studies will be done, by gene overexpression or knockdown in cell culture and analysis of activated signal transduction pathways. This project has critical clinical implications in that the effective treatment of breast carcinomas does rely on understanding drug-resistance at the molecular level.