A protein interaction landscape of breast cancer

• Published in: Science (American Association for the Advancement of Science) Vol. 374; no. 6563; p. eabf3066
• Main Authors: Kim, Minkyu, Park, Jisoo, Bouhaddou, Mehdi, Kim, Kyumin, Rojc, Ajda, Modak, Maya, Soucheray, Margaret, McGregor, Michael J, O'Leary, Patrick, Wolf, Denise, Stevenson, Erica, Foo, Tzeh Keong, Mitchell, Dominique, Herrington, Kari A, Muñoz, Denise P, Tutuncuoglu, Beril, Chen, Kuei-Ho, Zheng, Fan, Kreisberg, Jason F, Diolaiti, Morgan E, Gordan, John D, Coppé, Jean-Philippe, Swaney, Danielle L, Xia, Bing, van 't Veer, Laura, Ashworth, Alan, Ideker, Trey, Krogan, Nevan J
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 01.10.2021
• Subjects: 1-Phosphatidylinositol 3-kinase; Actomyosin; Adenosine diphosphate; Affinity; AKT protein; Apoptosis; Biomarkers; BRCA1 protein; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cancer research; Carcinogens; Cell Line, Tumor; Cell proliferation; Cellular communication; Chemotherapy; Deoxyribonucleic acid; Dephosphorylation; Disease; DNA; DNA damage; DNA repair; DNA sequencing; Double-strand break repair; Female; Gene mapping; Genes; Genetic Disorders; Genetics; Genomes; Genomics; Head & neck cancer; Heterogeneity; Humans; Isoforms; Kinases; Mass Spectrometry; Mathematical models; Mutants; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - isolation & purification; Neoplasm Proteins - metabolism; Networks; Patients; Phosphatase; Poly(ADP-ribose) polymerase; Protein Interaction Maps; Proteins; Purification; Repair; Rewiring; Ribose; Scientific imaging; Signal transduction; Spectroscopy; Statistical models; Tandem Affinity Purification; Toxicity; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abf3066

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.