Transforming Growth Factor beta (TGF beta) is the archetypal member of the TGF beta superfamily of ligands and has pleiotropic functions during normal development, adult tissue homeostasis and pathophysiological processes such as cancer. In epithelial cancers TGF beta signaling can either suppress tumor growth or promote metastasis via the induction of a well-characterized epithelial mesenchymal transition (EMT) program. We recently reported that PEAK1 kinase mediates signaling cross talk between TGF beta receptors and integrin/Src/MAPK pathways and functions as a critical molecular regulator of TGF beta-induced breast cancer cell proliferation, migration, EMT and metastasis. Here, we examined the breast cancer cell contexts in which TGF beta induces both EMT and PEAK1, and discovered this event to be unique to oncogene-transformed mammary epithelial cells and triple-negative breast cancer cells. Using the Cancer BioPortal database, we identified PEAK1 co-expressors across multiple malignancies that are also common to the TGF beta response gene signature (TBRS). We then used the ScanSite database to identify predicted protein protein binding partners of PEAKI and the PEAK1-TBRS co-expressors. Analysis of the Cytoscape interactome and Babelomics-derived gene ontologies for a novel gene set including PEAK1, CRK, ZEB1, IL11 and COL4A1 enabled us to hypothesize that PEAK1 may be regulating TGF beta-induced EMT via its interaction with or regulation of these other genes. In this regard, we have demonstrated that PEAKI is necessary for TGF beta to induce ZEB1-mediated EMT in the context of fibronectin/ITGB3 activation. These studies and future mechanistic studies will pave the way toward identifying the context in which TGF beta blockade may significantly improve breast cancer patient outcomes. (C) 2015 Elsevier Inc. All rights reserved.