Oncogenic signaling in amphiregulin and EGFR‐expressing PTEN‐null human breast cancer. Issue 2 (23rd October 2014)

• Record Type: Journal Article
• Authors: Kappler, Christiana S.; Guest, Stephen T.; Irish, Jonathan C.; Garrett-Mayer, Elizabeth; Kratche, Zachary; Wilson, Robert C.; Ethier, Stephen P.
• Is Part Of: Molecular oncology. Volume 9:Issue 2(2015:Feb.)
• Page Start: 527
• Page End: 543
• Publication Date: 2014-10-23
• Subjects: Triple‐negative breast cancer -- Epidermal growth factor receptor -- PTEN -- shRNA screen; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2014.10.006
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : A subset of triple negative breast cancer (TNBC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) 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 EGFR 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 β1. EGFR activity in this PTEN null background also results in Wnt/beta‐catenin signaling and activation of NF‐κB. In addition, AKT is constitutively phosphorylated in these cells and is resistant to gefitinib. Expression profiling demonstrated that AREG‐activated EGFR 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 EGFR, which likely mediates resistance to EGFR inhibitors. Highlights: Activation of EGFR by AREG alters signaling and gene expression compared to EGF. Activation of EGFR by AREG reduces mTORC1 pathway expression and phosphorylation. EGF‐positive, PTEN‐null TNBC cells are poised for Wnt/beta‐catenin signaling. Wnt/beta‐catenin activity occurs in a subset of cells and is enhanced in mammospheres. Regulation of growth/survival genes is uncoupled from EGFR in PTEN‐null TNBC cells.