自噬在氟伐他汀抑制三阴性乳腺癌转移中的作用及机制研究

Triple negative breast cancer(TNBC) is a subkind of breast cancer with high metastasis rate and poor prognosis. Besides chemotherapy drugs, no other theraputic drugs are available now. Statins can reduce the incidence of TNBC so we believe it is an ideal drug candidate for the treatment of TNBC. Further research in this field is still needed. Our preliminary data suggest that: fluvastatin decreased the invasion ability of MDA-MB-231 cells(231 cells, representing TNBC) ; fluvastatin up-regulated the expression of LC3-II protein in 231 cells; β-catenin,with is related to the metastasis character of 231cell, was decreased in 231 cells treated with fluvastatin. Since β-catenin has potential LIR motif, we assume that fluvastatin can inhibit the metastasis of 231 cells via selective autophagic degration of β-catenin. To testify our assumption, first of all, we will evalute the function of autophagy in fluvastatin treated 231 cells; besides, we will explore the role autophagy in the inhibition of metastasis by fluvastatin; also we will testify the role of autophagy in the downregulation of β-catenin; finally, we will evaluate the role of fluvastatin on the metastasis of TNBC in vivo. We hope our study will provide molecular mechanism for the adjuvant therapy of fluvastatin in TNBC and will provide a new method for treating TNBC.

三阴性乳腺癌的预后差，转移率高，除化疗药外无其他辅助治疗药物。他汀类药物可降低三阴性乳腺癌发病率，副作用小，有望用于辅助治疗，但理论依据尚不足。我们预实验结果显示：氟伐他汀干预下的三阴性乳腺癌细胞MDA-MB-231（231）的侵袭性降低、自噬水平升高、且β-catenin含量减少。鉴于β-catenin可促进肿瘤转移并含有潜在的自噬结合相关结构，我们假设氟伐他汀是通过自噬选择性降解β-catenin抑制231细胞转移。我们拟后续系统论证氟伐他汀在231细胞中诱导自噬；评估自噬在氟伐他汀抑制231细胞转移中的作用；探讨氟伐他汀作用下β-catenin降解与自噬的关系；并体内验证氟伐他汀通过调控自噬抑制三阴性乳腺癌转移。研究如获成功，将为氟伐他汀用于三阴性乳腺癌辅助治疗奠定理论，具有重要的临床意义和应用价值。

三阴性乳腺癌属于乳腺癌中预后较差的一个亚型，转移率高，目前除化疗外无其它有效的治疗方法。流行病学研究显示他汀类药物可以降低三阴性乳腺癌的发病率，但机制目前仍不明确。本研究在体外细胞水平，明确氟伐他汀（FL）对乳腺癌细胞系增殖、凋亡、迁移、侵袭等生物学特性的影响，明确氟伐他汀在乳腺癌细胞系中诱导自噬。研究进一步证实自噬在氟伐他汀抑制三阴性乳腺癌细胞转移中的作用，并探讨了β-catenin与自噬的相关性。此外，临床研究也证实乳腺癌患者血脂水平与淋巴结转移相关。本研究将进一步就氟伐他汀抑制乳腺癌转移的机制及其与自噬的关系进行研究。