A protein interaction landscape of breast cancer

Minkyu Kim, Jisoo Park, Mehdi Bouhaddou, Kyumin Kim, Ajda Rojc, Maya Modak, Margaret Soucheray, Michael J. McGregor, Patrick O'Leary, Denise Wolf, Erica Stevenson, Tzeh Keong Foo, Dominique Mitchell, Kari A. Herrington, Denise P. Muñoz, Beril Tutuncuoglu, Kuei Ho Chen, Fan Zheng, Jason F. Kreisberg, Morgan E. DiolaitiJohn D. Gordan, Jean Philippe Coppé, Danielle L. Swaney, Bing Xia, Laura van 't Veer, Alan Ashworth, Trey Ideker, Nevan J. Krogan

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numberabf3066
JournalScience
Volume374
Issue number6563
DOIs
StatePublished - Oct 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

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