The role of arachidonic acid in estrogen mediated mTOR activation

描述（由申请人提供）：在雌激素受体阳性（ER+）乳腺癌中，mTOR活性升高导致对常规化疗和激素治疗产生耐药性。已知雌激素及其膜相关雌激素受体独立于其在转录中的作用，有助于这种异常的mTOR活性。然而，其潜在机制尚不清楚。近年来，花生四烯酸（AA）及其代谢物被发现是雌激素非基因组作用的关键介质。根据这一发现，我们观察到乳腺癌患者肿瘤样本中AA水平和mTOR活性之间存在很强的相关性。这些观察结果表明，雌激素、AA和mTOR之间存在潜在的信号联系。这个探索性的R21项目旨在描述这种新型信号通路的分子基础。为了验证雌激素通过AA代谢级联激活mTOR的假说，我们计划开展三条研究线，包括确定：1)AA代谢级联在雌激素诱导mTOR激活中的作用，2)AA代谢产物参与mTOR调控，3)AA代谢产物激活mTOR的机制。这项研究的成功完成不仅将揭示mTOR激活的一种新的信号机制，而且还将进一步提高这种信号机制在乳腺癌治疗中的治疗意义。

DESCRIPTION (provided by applicant): In estrogen receptor positive (ER+) breast cancer, an elevated mTOR activity causes resistance to conventional chemo- and hormonal therapies. Estrogen and its membrane- associated estrogen receptors are known to contribute to this abnormal mTOR activity independent of their role in transcription. However, the underlying mechanism remains unknown. Recently, arachidonic acid (AA) and its metabolites have been found to serve as key mediators for the non-genomic action of estrogen. In concert with this finding, we have observed a strong correlation between AA level and mTOR activity in tumor samples from breast cancer patients. These observations suggest a potential signaling nexus that links estrogen, AA and mTOR. This exploratory R21 project is proposed to delineate the molecular basis for this novel signaling scheme. Three lines of investigation are planned to test the hypothesis that estrogen activates mTOR through the AA metabolic cascade, including determining: 1) the role of AA metabolic cascade in estrogen-induced mTOR activation, 2) the metabolites of AA involved mTOR regulation, and 3) the mechanism by which the metabolites of AA activate mTOR. Successful completion of the proposed research will not only shed light on a novel signaling mechanism for mTOR activation but also allow further elevation of the therapeutic implication of this signaling mechanism in breast cancer treatment.