美她司酮调控Cyr61在抑制乳腺癌细胞粘附、侵袭、转移中的作用机制

Invasion and metastasis are the most life-threatening aspects of triple-negative breast cancer (TNBC). Developing more effective anti-metastasis drugs is important to breast cancer research. Large clinical trials have suggested that oral contraceptives can have important effects on cancer prevention. Our previous studies showed that, metapristone, the most predominant metabolite of mifepristone, can effectively inhibit cancer metastasis. However, the mechanism involved in mediating such an effect remains unclear. In our previous study, we applied a comparative proteomic approach to the analysis of differentially expressed proteins in the TNBC cells following treatment with metapristone. Cyr61, a member of the CCN family of secreted matricellular proteins, was down-regulated significantly and identified by MALDI-TOF-TOF. In the present study, we aim to extensively analyze the role of Cyr61 in the mechanism of metapristone inhibiting breast cancer cell invasion and metastasis. We will check whether metapristone inhibits the expression of Cyr61 by antagonizing the glucocorticoid receptor, affects the integrin signal pathway by regulating Cyr61, and further affects the formation and activation of focal adhesion related complex. This research has important theoretical value and guiding significance of drug development against metastasis, provides new clues for metastasis mechanism of TNBC, and will improve the level of treatment of triple negative breast cancer.

癌细胞侵袭转移是三阴性乳腺癌（TNBC）患者死亡的主要原因，研发有效抑制TNBC转移的药物是乳腺癌研究亟待解决的问题。国外研究机构大规模的临床调查表明，口服避孕药具有明显的癌症预防作用。我们前期的研究发现口服避孕药米非司酮主要活性代谢产物美她司酮对TNBC细胞的粘附侵袭力具有明显抑制效果，但其作用机制尚不清楚。本课题拟在前期药物分泌蛋白质组学研究基础上，探讨富含半胱氨酸的细胞分泌蛋白Cyr61在美她司酮抑制TNBC细胞粘附侵袭中的作用机制，分析美她司酮对Cyr61的抑制作用是否与糖皮质激素受体相关，以及美她司酮是否通过Cyr61调控整合素信号通路，影响黏附相关复合物的形成与活性，从而抑制TNBC细胞的粘附侵袭，抵抗乳腺肿瘤的转移。本课题对抗肿瘤转移药物的研究具有重要的理论价值和指导意义，对揭示三阴性乳腺癌转移的分子机制、提高我国三阴性乳腺癌的治疗水平具有重要意义。

我们的研究发现，口服避孕药米非司酮主要活性代谢产物美她司酮，对三阴性乳腺癌（TNBC）细胞的粘附侵袭力具有明显抑制效果。通过分泌蛋白质组学研究，结合免疫共沉淀，细胞迁移与粘附实验，以及动物学实验，我们发现，美她司酮能通过抑制富含半胱氨酸的细胞分泌蛋白CYR61，调控整合素αvβ1信号通路，影响复合物CYR61/integrin αvβ1的形成与活性，从而抑制TNBC细胞的粘附侵袭，抵抗乳腺肿瘤的转移。本课题研究成果为发现肿瘤转移标志物提供了新的研究思路，对抗肿瘤转移药物的研发具有重要的理论价值和指导意义，对揭示三阴性乳腺癌转移的分子机制、提高我国三阴性乳腺癌的治疗水平具有重要意义。在该项目资助下，目前已发表SCI论文5篇，在投2篇，申请PCT专利一项。培养博硕士各两名。