Caveolin-1介导乳腺癌干细胞化疗抵抗及干性维持的作用和分子机制研究

肿瘤干细胞具有高度耐药性，并富集表达ABC转运蛋白，解析肿瘤干细胞耐药的关键分子及调控通路成为逆转耐药的新思路。Caveolin-1是细胞小窝的主要构成及功能蛋白，其在细胞信号转导及肿瘤发展过程中发挥枢纽作用，但目前其与肿瘤干细胞及耐药调控的关系尚不清楚。我们前期研究发现caveolin-1在乳腺癌干细胞上富集表达，其表达抑制可显著增加干细胞内化疗药物含量并促进其分化，同时与β-catenin/ABCG2信号通路正性相关，由此我们设想caveolin-1可通过β-catenin/ABCG2通路介导乳腺癌干细胞耐药并调控其更新分化能力。本项目拟通过体内外基因重组、流式分选及三维培养等技术探讨caveolin-1调控乳腺癌干细胞耐药的关键作用及其对更新分化能力的影响，并解析caveolin-1调控β-catenin/ABCG2信号通路的分子机制。研究的开展将为耐药预防或化疗增敏提供新策略。

Multidrug resistance-induced chemotherapy failure and metastasis are the main reasons leading to breast cancer death. Recent numerous studies demonstrated that cancer stem cells (CSCs) had strong drug resistance ability and enriched expression of ABC transporters. Identification and characterization of critical signalings involved in regulating CSCs’ drug resistance has become a hot direction in improving chemotherapeutic efficacy. Caveolin-1 is the essential constituent protein of specialized membrane invaginations called caveolae. Numerous findings indicated that caveolin-1 acted as a molecular hub integrating multiple molecules implicated in cancer development. However, the significance of caveolin-1 in regulating CSCs and drug resistance is largely remained unknown. Our preliminary study found that caveolin-1 had enriched expression on breast CSCs and was significantly elevated after chemotherapy both in vitro and in vivo. Caveolin-1 silencing could greatly promote drug influx in breast CSCs and enhance their differentiation. Meanwhile, clinical study also demonstrated that caveolin-1 was positively correlated to β-catenin/ABCG2 pathway. Therefore we hypothesized that caveolin-1 could promote breast cancer drug resistance and regulate CSCs fate decision through activating β-catenin/ABCG2 signaling. To confirm the hypothesis, this proposal will include three special objectives: (1) To validate whether caveolin-1 can regulate breast CSCs drug resistance and self-renewal in vitro and in vivo; (2) To test the influences of caveolin-1 on breast CSCs’ differentiation and its role in regulating drug resistance; (3) To explore the molecular interactions and pathways between caveolin-1 and β-catenin/ABCG2 signaling. If the hypothesis can be validated, we will not only provide novel strategies for preventing drug resistance or chemosensitization, but also benefit for improving breast cancer chemotherapeutic efficacy and clinical outcomes.