BRCA1 deficiency in ovarian cancer is associated with alteration in expression of several key regulators of cell motility – A proteomics study

Functional loss of expression of breast cancer susceptibility gene 1(<i>BRCA1</i>) has been implicated in genomic instability and cancer progression. There is emerging evidence that <i>BRCA1</i> gene product (BRCA1) also plays a role in cancer cell migration. We performed a quantitative proteomics study of EOC patient tumor tissues and identified changes in expression of several key regulators of actin cytoskeleton/cell adhesion and cell migration (CAPN1, 14-3-3, CAPG, PFN1, SPTBN1, CFN1) associated with loss of BRCA1 function. Gene expression analyses demonstrate that several of these proteomic hits are differentially expressed between early and advanced stage EOC thus suggesting clinical relevance of these proteins to disease progression. By immunohistochemistry of ovarian tumors with BRCA1^+/+ and BRCA1^null status, we further verified our proteomic-based finding of elevated PFN1 expression associated with BRCA1 deficiency. Finally, we established a causal link between PFN1 and BRCA1-induced changes in cell migration thus uncovering a novel mechanistic basis for BRCA1-dependent regulation of ovarian cancer cell migration. Overall, findings of this study open up multiple avenues by which BRCA1 can potentially regulate migration and metastatic phenotype of EOC cells.

乳腺癌易感基因1 (BRCA1) 的表达功能缺失已被证实与基因组不稳定及癌症进展密切相关。越来越多的证据表明，BRCA1基因编码的蛋白（BRCA1）同样参与癌细胞迁移过程。本研究针对上皮性卵巢癌（epithelial ovarian cancer, EOC）患者的肿瘤组织开展了定量蛋白质组学研究，鉴定出与BRCA1功能缺失相关的肌动蛋白细胞骨架/细胞黏附及细胞迁移的多个关键调控因子的表达变化，相关因子包括CAPN1、14-3-3、CAPG、PFN1、SPTBN1、CFN1。基因表达分析显示，上述蛋白质组学筛选得到的候选靶点中有多个在早期与晚期上皮性卵巢癌组织中存在差异表达，提示这些蛋白与疾病进展具有临床相关性。通过对BRCA1野生型（BRCA1^+/+）与BRCA1缺陷型（BRCA1^null）卵巢肿瘤开展免疫组织化学检测，本研究进一步验证了“BRCA1缺陷伴随PFN1表达升高”这一基于蛋白质组学的研究发现。最终，本研究证实了PFN1与BRCA1介导的细胞迁移变化之间存在因果关联，从而揭示了BRCA1依赖性调控卵巢癌细胞迁移的全新分子机制。总体而言，本研究的发现为BRCA1调控上皮性卵巢癌细胞迁移及转移表型提供了多条潜在研究方向。