Wnt5a对三阴性乳腺癌转移的治疗作用和分子机制

Triple negative breast cancer(TNBC) is always considered as the most tough type in breast cancer and most of patients died of its high rate of metastasis. Lack of specific target therapy and effective animal model are the key problems. Previous study has shown that expression of Wnt5a is positively correlated to clinical therapeutic effects for estrogen receptor negative patients. It has also been reported that exogenous Wnt5a could inhibit metastasis of breast cancer cells, especially for the late stage of the disease. For the metastasis of TNBC, our previous study has shown for the first time that Wnt5a has significant inhibitory effects on its metastasis. Our project would use two model systems: constructed stable cell lines and primary cells freshly extracted from patients, through overexprssion of human Wnt5a and conditioned medial rich with Wnt5a treatment, to confirm the inhibitory effects of Wnt5a on TNBC metastasis. Based on the results we have from the microarray and RNA-Seq, we would focus on the mechanism for Wnt5a to regulate Mmp13 expression to affect tumor metastasis, therefore, to provide potential pharmaceutical targets for TNBC treatments.

雌激素受体，孕激素受体和人表皮生长因子受体均阴性的三阴性乳腺癌是乳腺癌治疗中最棘手的一类疾病,绝大多数病人死于其高转移性，但对机制缺乏了解，故无具体的治疗靶点。研究表明单独雌激素受体阴性的乳腺癌病人中，Wnt5a 表达水平与临床治疗效果显著正相关。尤其对于乳腺癌晚期转移,给予外源Wnt5a可起到显著抑制作用。我们前期研究结果首次提示，Wnt5a对三阴性乳腺癌的转移也具有抑制作用。因此，本项目拟采用乳腺癌细胞系和肿瘤病人的原代细胞两个模型系统，通过细胞系稳定过表达Wnt5a和富含Wnt5a条件培养液处理原代细胞等手段，证明Wnt5a确实对三阴性乳腺癌转移具有显著抑制功能。然后在前期获得的芯片和RNA序列分析结果基础上，探究Wnt5a通过调控肿瘤转移重要靶分子Mmp13来抑制三阴性乳腺癌转移的详细机制，为该病的治疗提供理论依据和药物靶点。