Beyond genomics: biologic insights from the CPTAC proteogenomic analysis of breast cancer

Global genomic investigations of breast cancers have generated an extensive catalogue of somatic mutations as potential therapeutic targets. However, progress has been slow in differentiating driver mutations from passenger mutations, which hindered the development of therapeutic hypothesis. Proteomic analysis allows an opportunity for functional interpretation of somatic mutations (1). The initial proteomic analysis performed in the Cancer Genome Atlas (TCGA) breast cancer study quantified the expression levels of 171 cancer-related proteins and phosphoproteins by using the antibody based reverse phase protein array (RPPA) platform on 403 tumors, which identified seven proteomic subtypes, including Basal, HER2, Lum A, Lum A/B, that were highly concordant with the mRNA subtypes (2), and Reac I (mostly composed of a subset of mRNA Lum A tumors), and Reac II subtypes (a mixture of mRNA subtypes) that were enriched by proteins such as fibronectin, caveolin 1 and collagen VI, likely produced by the microenvironment and/or cancer-activated fibroblasts, as well as a seventh proteomic subtype “X”, which contained too few cases to analyzed (3).