Oncogenic signaling in amphiregulin and EGFR-expressing PTEN-null human breast cancer

A subset of triple negative breast cancer (TNBC) is characterized by overexpression of the epidermal growth factor receptor (EGER) and loss of PTEN, and patients with these determinants have a poor prognosis. We used cell line models of EGFR-positive/PTEN null TNBC to elucidate the signaling networks that drive the malignant features of these cells and cause resistance to EGER inhibitors. In these cells, amphiregulin (AREG)-mediated activation of EGFR results in up-regulation of fibronectin (FN1), which is known to be a mediator of invasive capacity via interaction with integrin beta 1. EGFR activity in this PTEN null background also results in Wnt/beta-catenin signaling and activation of NF-kappa B. In addition, AKT is constitutively phosphorylated in these cells and is resistant to gefitinib. Expression profiling demonstrated that AREG-activated EGER regulates gene expression differently than EGF-activated EGFR, and functional analysis via genome-scale shRNA screening identified a set of genes, including PLK1 and BIRC5, that are essential for survival of SUM-149 cells, but are uncoupled from EGFR signaling. Thus, our results demonstrate that in cells with constitutive EGFR activation and PTEN loss, critical survival genes are uncoupled from regulation by EGER, which likely mediates resistance to EGFR inhibitors. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.