First large-scale proteogenomic study of breast cancer provides insight into potential therapeutic targets

First large-scale proteogenomic study of breast cancer provides insight into potential therapeutic targets

Appearing in Nature, the study illustrates the power of integrating genomic and proteomic data to yield a more complete picture of cancer biology than either analysis could do alone.

The effort produced a broad overview of the landscape of the proteome (all the proteins found in a cell) and the phosphoproteome (the sites at which proteins are tagged by phosphorylation, a chemical modification that drives communication in the cell) across a set of 77 breast cancer tumors that had been genomically characterized.

The researchers analyzed breast tumors using accurate mass, high-resolution mass spectrometry, a technology that extends the coverage of the proteome far beyond the coverage that can be achieved by traditional antibody-based methods. This allowed them to scale their efforts and quantify more than 12,000 proteins and 33,000 phosphosites, an extremely deep level of coverage.

This analysis uncovered new protein markers and signaling pathways for breast cancer subtypes and tumors carrying frequent mutations such as PIK3CA and TP53 mutations. The team also correlated copy number alterations (extra or missing DNA) in some genes with protein levels, allowing them to identify 10 new candidate regulators. Two of these candidate genes, SKP1 and CETN3, can be connected to the oncogene EGFR, which is a marker for a particularly aggressive breast cancer subtype, known as "basal-like" tumors.

Using transcriptional (mRNA) profiling, scientists have divided breast cancer into four major subtypes: luminal A and B subtypes, basal-like tumors, and HER2-enriched tumors. In this work, the researchers used proteomic and phosphoproteomic data to recapitulate basal and luminal subtypes. They were also able to identify a stromal-enriched cluster and, by clustering tumors based on phosphorylation pathways, they highlighted a G-protein-coupled receptor subgroup not seen with mRNA approaches.

In the study and treatment of breast cancer, scientists and physicians hope to identify more druggable kinase proteins in addition to HER2, which can be targeted with trastuzumab (Herceptin) but only in 20 percent of breast cancers that overexpress the HER2 protein. In this study, the researchers conducted an outlier analysis of the phosphorylation states of kinase enzymes, which highlighted aberrantly activated kinases in breast cancer samples, such as HER2, CDK12, PAK1, PTK2, RIPK2 and TLK2.