The role of arachidonic acid in estrogen mediated mTOR activation

描述(申请人提供)：在雌激素受体阳性(ER+)乳腺癌中，mTOR活性升高会导致对传统化疗和激素治疗的抵抗。已知雌激素及其膜相关雌激素受体对这种异常的mTOR活性有贡献，而不是依赖于它们在转录中的作用。然而，其潜在的机制仍不清楚。近年来，花生四烯酸(AA)及其代谢产物被发现是雌激素非基因组作用的关键介体。与这一发现一致的是，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项目被提出来描述这一新的信号机制的分子基础。为了验证雌激素通过AA代谢级联途径激活mTOR的假说，计划进行三个方面的研究，包括：1)AA代谢级联在雌激素诱导的mTOR激活中的作用，2)AA代谢产物参与mTOR调节，以及3)AA代谢产物激活mTOR的机制。这项拟议研究的成功完成不仅将阐明mTOR激活的一种新的信号机制，而且还将进一步提高该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.