A new class of protein cancer biomarker candidates: differentially expressed splice variants of ERBB2 (HER2/neu) and ERBB1 (EGFR) in breast cancer cell lines.

Combined RNA-Seq and proteomics analyses reveal striking differential expression of splice isoforms of key proteins in important cancer pathways and networks. Even between primary tumor cell lines from histologically similar inflammatory breast cancers, we find striking differences in hormone receptor-negative cell lines that are ERBB2 (Her2/neu)-amplified versus ERBB1 (EGFR) over-expressed with low ERBB2 activity. We have related these findings to protein-protein interaction networks, signaling and metabolic pathways, and methods for predicting functional variants among multiple alternative isoforms. Understanding the upstream ligands and regulators and the downstream pathways and interaction networks for ERBB receptors is certain to be important for explanation and prediction of the variable levels of expression and therapeutic responses of ERBB+tumors in the breast and in other organ sites. Alternative splicing is a remarkable evolutionary development that increases protein diversity from multi-exonic genes without requiring expansion of the genome. It is no longer sufficient to report the up- or down-expression of genes and proteins without dissecting the complexity due to alternative splicing. This article is part of a Special Issue entitled: 20Years of Proteomics in memory of Viatliano Pallini. Guest Editors: Luca Bini , Juan J. Calvete, Natacha Turck, Denis Hochstrasser and Jean-Charles Sanchez.