The protein interaction landscape of breast cancer

Cancers have been associated with diverse sets of genomic alterations, many of which are rare with uncertain significance. To understand the cellular mechanisms impacted by such alterations in breast invasive carcinoma, we have applied affinity-purification mass spectrometry to delineate comprehensive biophysical interaction networks for 40 frequently altered breast cancer proteins. These networks interconnect and enrich for common and rare cancer mutations; they are also substantially re-wired by mutations, including in TP53 and PIK3CA, and across cancerous and non-cancerous cell contexts. Our analysis identifies a novel AKT-interacting protein, S100A3, which we find activates AKT signaling and is predictive of clinical response to AKT inhibitors. Similarly, UBE2N emerges as a BRCA1 interactor predictive of clinical response to inhibition of PARP. Finally, we show that Spinophilin interacts with and dephosphorylates BRCA1 to promote DNA double strand break repair. Thus, cancer protein interaction landscapes provide a framework for recognizing oncogenic drivers and drug vulnerabilities.