FGD5 维持肿瘤干细胞样性状促进三阴性乳腺癌发病及疾病进展的作用及机制研究

大多数三阴性乳腺癌（TNBC）由于复发率较高且缺乏针对性治疗方法，预后较其他乳腺癌亚型患者更差。因此，寻找和探索针对TNBC有效的靶向疗法迫在眉睫。肿瘤起始细胞（TICs）在乳腺癌及其它恶性肿瘤的耐药、复发和转移中起关键作用，靶向TICs被认为是有效抑制乳腺癌的新策略和新方法。我们近期发现，FGD5在TNBC中高表达且与其不良预后密切相关。敲除FGD5抑制TNBC肿瘤细胞的生长、侵袭和干性能力，并下调EGFR的表达及其下游信号通路。此外，小鼠乳腺上皮细胞特异性敲除FGD5后干细胞数量及活性明显降低，乳腺重构能力减弱。机制上，我们发现FGD5与EGFR发生相互作用并妨碍EGFR泛素化水平。为此，我们将从临床数据、分子、细胞和动物水平研究FGD5在TNBC细胞中调节EGFR表达，维持TICs特征进而促进乳腺癌发生发展的作用及机制。该研究将为TNBC关键靶点的发现及疾病治疗提供新的策略。

Most triple-negative breast cancers (TNBCs) have the worst prognosis and distant metastasis-free survival among breast cancer subtypes. Currently, no targeted therapies are available for TNBC patients due to their lack of reliable and effective molecular targets. Therefore, it is urgent to find and explore effective targeted therapy for TNBC. Tumor initiating cells (TICs) play a key role in drug resistance, recurrence and metastasis of breast cancer and other malignant tumors. Targeting TICs is considered as a new strategy for effectively inhibiting breast cancer. Here, we showed that Faciogenital Dysplasia 5 (FGD5) was highly expressed in TNBC subtype of breast cancer and correlated with bad prognosis in TNBCs. FGD5 deletion inhibited TNBC cell proliferation, invasion and self-renewal, especially reduced the expression of epidermal growth factor receptor (EGFR) and inhibited its downstream signaling. Furthermore, FGD5 knockout in mouse mammary epithelial cells significantly reduced the number and activity of mammary stem cells (MaSC), and subsequently decreased the repopulation frequency of MaSC in limiting dilution cleared–fat-pad repopulation assay. Mechanistically, FGD5 interacted with EGFR to impede the ubquitination of EGFR. Based on these findings, we intend to use cell models, transgenic animal models, PDX models and clinical data to investigate the role of FGD5 in TNBC development and progression, and the molecular mechanism by which FGD5 interacts with EGFR to support cancer stem cell traits. Our study may not only provide insights into the pathogenesis of TNBC, but also provide clues and strategies for the development of anti-TNBC agents.