乳腺癌是女性发病率最高的恶性肿瘤，约70%为雌激素受体（ER）阳性，因此针对ER的内分泌治疗策略在乳腺癌治疗中尤为重要。他莫昔芬是乳腺癌内分泌治疗的重要药物，但长期应用他莫昔芬易产生耐药，最终导致肿瘤的复发和转移。他莫昔芬的耐药机制异常复杂，虽然经过大量研究，其耐药机制仍未完全阐明。申请人长期从事乳腺癌耐药机制研究，并建立了稳定的具有他莫昔芬耐药性的乳腺癌细胞株。基于细胞因子芯片筛选，我们近期发现他莫昔芬耐药细胞可以主动分泌肝细胞生长因子（HGF），并通过激活HGF/c-MET-HOTAIR反馈调控环路，促进乳腺癌细胞获得他莫昔芬耐药性。本项目拟在此基础上，进一步在细胞和动物在体水平，揭示这一反馈环路在乳腺癌细胞获得他莫昔芬耐药性过程中的生物学功能，解析这一反馈调控环路的分子机制，并结合临床标本和预后相关性分析等，阐明该环路的临床意义，为乳腺癌他莫昔芬耐药的临床治疗提供新的药物干预靶点。

Breast cancer is the most malignant tumor in women. About 70% of breast cancers are estrogen receptor (ER) positive, therefore the endocrine therapy strategy targeting ER is particularly important in the treatment of breast cancer. Tamoxifen is one of most important endocrine therapeutic drugs of breast cancer. Tamoxifen can inhibit the proliferation of ER positive breast cancer cells by blocking the downstream signaling of ER. However, long-term treatment of tamoxifen will finally cause drug resistance, eventually leading to tumor recurrence and metastasis. The resistance mechanism of tamoxifen was extremely complexed. It’s not clarified yet so far. We focused on the mechanism research of breast cancer drug resistance and established several cell lines with stable tamoxifen resistance. Our previous studies found that tamoxifen resistant cells could actively secrete hepatocyte growth factor (HGF) according to cytokine array screening, and activate HGF/c-MET-HOTAIR feedback regulatory loop to induce the tamoxifen resistance. Our present project is proposed to elucidate the molecular mechanisms of HGF/c-MET-HOTAIR feedback regulatory loop in detail. Then we analyze its biological function and clinical significance in cells, animal in vivo, clinical tissue specimens and clinical prognosis correlation respectively. Our work will uncover the mechanism of HGF/c-MET-HOTAIR regulatory loop to induce tamoxifen resistance in ER positive breast cancer cells, and further provide the novel duggable targets to anti-tamoxifen resistance.