VHL基因调控三阴乳腺癌细胞迁徙及化疗敏感性的作用及机制研究

三阴乳腺癌（triple-negative breast cancer，TNBC）是最为难治、患者死亡率最高的乳腺癌亚型。大部分患者在初次诊断时就已经出现了淋巴结转移，导致5年生存率低于30%。因此，发现和解析调控三阴乳腺癌转移的生物学途径成为乳腺癌研究领域中的热点和关键科学问题。本课题组在前期研究中，发现VHL抑癌基因高表达的患者反而生存率更低。为了解释这一看似矛盾的现象，我们提出了VHL可能调控三阴乳腺癌肿瘤细胞迁移及化疗药物敏感性的猜想。前期工作中，我们初步验证了VHL阴性细胞自身迁移能力增强，并同时可以通过外泌体途径增加VHL阳性细胞的迁徙能力，但同时也发现VHL阴性细胞对化疗药物更敏感。在所拟研究中，我们将围绕VHL基因调控细胞迁徙的内在、外在机理，以及铂类化疗药物敏感性进行深入研究。本项目的执行，有希望揭示三阴乳腺癌转移的关键作用基因和生物学途径。

Triple-negative breast cancer (TNBC) is the most deadly subtype of breast cancer worldwide due to its highly metastatic nature.The mechanisms how the cellular motility is enhanced in TNBC is not well understood.In our preliminary studies, we analyzed patient survival information and driver gene status.Surprisingly, we found that the expression level of VHL, a known tumor suppressor gene, is negatively correlated with patient survival.To explain this conundrum, we hypothesized that VHL might simultaneously regulates TNBC cell motility and sensitivity to chemotherapy.Indeed, we found that VHL knockout promotes intrinsic cell motility, but also enhance exosome pathway to enhance the mobility of VHL wild-type recipient cells.Meanwhile, VHL knockout renders cells more vulnerable to carboplatinum.In this proposal, we aim to extend our initial observation to provide mechanistic insights on how VHL regulates TNBC cell motility and drug sensitivity.