内分泌治疗是雌激素受体阳性乳腺癌的经典治疗方案，但很多患者显示出耐药性。与初次治疗相比，耐药乳腺癌组织的代谢通路有显著变化，暗示靶向相关代谢异常途径可作为治疗肿瘤耐药的方法。我们的前期研究发现FDXR通过正调节CPT1A介导的脂肪酸氧化分解途径（FAO），增强细胞线粒体功能及生长增殖。与原代乳腺癌细胞相比，耐药型乳腺癌细胞更加依赖于FDXR-CPT1A-FAO信号轴，我们推测此信号轴参与了内分泌治疗耐药。本项目拟从以下两个方面展开研究：1. 鉴定FDXR酶活性在调节乳腺癌细胞线粒体功能及生长增殖过程中的作用，以及FDXR调节CPT1A转录表达的分子机制。2. 研究FDXR-CPT1A-FAO信号轴参与内分泌治疗耐药的分子调节机制，以及与机体内分泌治疗耐药的生理相关性。该项目的成功完成有助于阐明代谢重编辑以促进内分泌治疗耐药发生发展的分子调节机制，也为内分泌治疗耐药的难点提供新的分子靶标。

Breast cancer is the leading cause of cancer death among women. Approximately 75% of breast cancer is estrogen receptor positive (ER+) and this leads to the majority of breast cancer deaths. Despite treatment with anti-estrogen therapy, up to 50% of patients have de novo resistance to endocrine therapy, and also up to 50% patients with ER+ advanced breast cancer relapse after treatment, highlighting the need for additional effective therapies. Altered metabolism is a hallmark of cancer and understanding how cells adjust their metabolism to support uncontrolled tumor growth is critical for the development of effective and specific therapeutic targets. Our preliminary study showed that ferredoxin reductase (FDXR) potentiates ER+ breast cancer endocrine resistance via carnitine palmitoyltransferase 1A (CPT1A)-mediated fatty acid oxidation (FAO). We will tackle the following overarching challenges: how FDXR regulates mitochondrial oxidative phosphorylation in ER+ breast cancer, and how FDXR-CPT1A-FAO axis contributes to endocrine resistance in ER+ breast cancer. The specific aims of this project include: 1) investigate whether FDXR enzymatic activity regulates mitochondrial function, and in turn, cell proliferation and tumor growth in ER+ breast cancer, and understand the molecular mechanism of how FDXR regulates CPT1A expression; 2) investigate how FDXR-CPT1A-FAO axis potentiates endocrine resistance in ER+ breast cancer, and determine the functional significance of FDXR-CPT1A-FAO axis in endocrine resistant breast cancer xenograft mice models. These studies will not only reveal an important mechanism of how altered mitochondrial metabolism facilitates ER+ breast cancer to survive endocrine treatment, but also set the stage for development of novel anti-cancer approaches.