Activating PIK3CA Mutations Induce an Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-regulated Kinase (ERK) Paracrine Signaling Axis in Basal-like Breast Cancer.

Young CD, Zimmerman LJ, Hoshino D, Formisano L, Hanker AB, Gatza ML, Morrison MM, Moore PD, Whitwell CA, Dave B, Stricker T, Bhola NE, Silva GO, Patel P, Brantley-Sieders DM, Levin M, Horiates M, Palma NA, Wang K, Stephens PJ, Perou CM, Weaver AM, O'Shaughnessy JA, Chang JC, Park BH, Liebler DC, Cook RS, Arteaga CL
Mol Cell Proteomics. 2015 14 (7): 1959-76

PMID: 25953087 · PMCID: PMC4587316 · DOI:10.1074/mcp.M115.049783

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) have been shown to transform human mammary epithelial cells (MECs). These mutations are present in all breast cancer subtypes, including basal-like breast cancer (BLBC). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified 72 protein expression changes in human basal-like MECs with knock-in E545K or H1047R PIK3CA mutations versus isogenic MECs with wild-type PIK3CA. Several of these were secreted proteins, cell surface receptors or ECM interacting molecules and were required for growth of PIK3CA mutant cells as well as adjacent cells with wild-type PIK3CA. The proteins identified by MS were enriched among human BLBC cell lines and pointed to a PI3K-dependent amphiregulin/EGFR/ERK signaling axis that is activated in BLBC. Proteins induced by PIK3CA mutations correlated with EGFR signaling and reduced relapse-free survival in BLBC. Treatment with EGFR inhibitors reduced growth of PIK3CA mutant BLBC cell lines and murine mammary tumors driven by a PIK3CA mutant transgene, all together suggesting that PIK3CA mutations promote tumor growth in part by inducing protein changes that activate EGFR.

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (26)

Amphiregulin Animals Breast Neoplasms Cell Line, Tumor Cell Proliferation Chromatography, Liquid Class I Phosphatidylinositol 3-Kinases Disease-Free Survival Down-Regulation Epidermal Growth Factor ErbB Receptors Extracellular Matrix Extracellular Signal-Regulated MAP Kinases Female Humans Mice, Nude Mutation Neoplasm Proteins Paracrine Communication Phosphatidylinositol 3-Kinases Protein Binding Protein Kinase Inhibitors Proteomics Signal Transduction Tandem Mass Spectrometry Up-Regulation

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