Cancers have been associated with a diverse array of genomic alterations. To help mechanistically understand such alterations in breast-invasive carcinoma, we applied affinity purification–mass spectrometry to delineate comprehensive biophysical interaction networks for 40 frequently altered breast cancer (BC) proteins, with and without relevant mutations, across three human breast cell lines. These networks identify cancer-specific protein-protein interactions (PPIs), interconnected and enriched for common and rare cancer mutations, that are substantially rewired by the introduction of key BC mutations. Our analysis identified BPIFA1 and SCGB2A1 as PIK3CA-interacting proteins, which repress PI3K-AKT signaling, and uncovered USP28 and UBE2N as functionally relevant interactors of BRCA1. We also show that the protein phosphatase 1 regulatory subunit spinophilin interacts with and regulates dephosphorylation of BRCA1 to promote DNA double-strand break repair. Thus, PPI landscapes provide a powerful framework for mechanistically interpreting disease genomic data and can identify valuable therapeutic targets.

中文翻译：

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乳腺癌的蛋白质相互作用景观

癌症与多种基因组改变有关。为帮助从机制上理解浸润性乳腺癌中的此类改变，我们应用亲和纯化-质谱法描绘了三种人类乳腺细胞系中 40 种频繁改变的乳腺癌 (BC) 蛋白（有或没有相关突变）的综合生物物理相互作用网络。这些网络识别癌症特异性蛋白质-蛋白质相互作用 (PPI)，它们相互关联并丰富了常见和罕见的癌症突变，这些突变在引入关键 BC 突变后实质上重新连接。我们的分析将 BPIFA1 和 SCGB2A1 鉴定为 PIK3CA 相互作用蛋白，它们抑制 PI3K-AKT 信号，并发现 USP28 和 UBE2N 是 BRCA1 的功能相关相互作用因子。我们还表明蛋白磷酸酶 1 调节亚基亲旋蛋白与 BRCA1 相互作用并调节 BRCA1 的去磷酸化以促进 DNA 双链断裂修复。因此，PPI 景观为机械解释疾病基因组数据提供了一个强大的框架，并且可以识别有价值的治疗目标。