Mechanism of Aromatase Inhibitor Resistance

芳香酶抑制剂耐药机制

• 批准号: 7151643
• 负责人: Selma Masri
• 金额: $ 2.79万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-28 至 2010-08-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151643
• 关键词: aromatase inhibitors; breast neoplasms; cell line; drug resistance; genes

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.

描述(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，就像所有延长药物治疗一样，耐药性确实是通过一种目前未知的机制产生的。该实验室假设，对芳香酶抑制剂的抗药性确实需要另一条信号通路，使细胞能够适应抑制剂的存在，但仍能进行正常的细胞增殖。为了解决这个问题，该实验室培育了对芳香酶抑制剂和抗雌激素他莫昔芬具有抗药性的MCF-7aro(芳香酶过度表达)乳腺癌细胞株。1.为了研究与芳香酶抑制剂耐药相关的候选基因，本实验室拟对MCF-7aro耐药细胞系进行基因芯片分析。2.为了更好地了解基因芯片鉴定的基因如何参与芳香酶抑制剂的抗性，将通过细胞培养中基因的过度表达或敲除以及对激活的信号转导途径的分析，进一步进行机制研究。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。