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

Abstract

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.

• Authors: Christian D Young, Lisa J Zimmerman, Daisuke Hoshino, Luigi Formisano, Ariella B Hanker, Michael L Gatza, Meghan M Morrison, Preston D Moore, Corbin A Whitwell, Bhuvanesh Dave, Thomas Stricker, Neil E Bhola, Grace O Silva, Premal Patel, Dana M Brantley-Sieders, Maren Levin, Marina Horiates, Norma A Palma, Kai Wang, Philip J Stephens, Charles M Perou, Alissa M Weaver, Joyce A O'Shaughnessy, Jenny C Chang, Ben Ho Park, Daniel C Liebler, Rebecca S Cook, Carlos L Arteaga
• Journal: Molecular & cellular proteomics : MCP (Mol Cell Proteomics) Vol. 14 Issue 7 Pg. 1959-76 (Jul 2015) ISSN: 1535-9484 [Electronic] United States
• PMID: 25953087 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Amphiregulin
• Neoplasm Proteins
• Protein Kinase Inhibitors
• Epidermal Growth Factor
• Phosphatidylinositol 3-Kinases
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• EGFR protein, human
• ErbB Receptors
• Extracellular Signal-Regulated MAP Kinases

Topics

• Amphiregulin (metabolism)
• Animals
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chromatography, Liquid
• Class I Phosphatidylinositol 3-Kinases
• Disease-Free Survival
• Down-Regulation (drug effects)
• Epidermal Growth Factor (pharmacology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Extracellular Matrix (drug effects, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Humans
• Mice, Nude
• Mutation (genetics)
• Neoplasm Proteins (metabolism)
• Paracrine Communication (drug effects)
• Phosphatidylinositol 3-Kinases (genetics)
• Protein Binding (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proteomics
• Signal Transduction (drug effects)
• Tandem Mass Spectrometry
• Up-Regulation (drug effects)