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Mol Cell Proteomics. 2015 Jul;14(7):1959-76. doi: 10.1074/mcp.M115.049783. Epub 2015 May 7.

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

Author information

1
From the Departments of ‡Medicine.
2
§Biochemistry, ‡‡Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt University School of Medicine, Nashville, Tennessee;
3
¶Cancer Biology.
4
¶¶Departments of Pathology and Laboratory Medicine and Genetics; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina;
5
‡‡Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt University School of Medicine, Nashville, Tennessee;
6
§§Houston Methodist Cancer Center, Houston, Texas;
7
‖Pathology, Microbiology and Immunology; **Breast Cancer Research Program; Vanderbilt Ingram Cancer Center, Nashville, Tennessee;
8
Baylor Charles A. Sammons Cancer Center, Dallas, Texas;
9
Foundation Medicine, Cambridge, Massachusetts.
10
¶Cancer Biology, ‖Pathology, Microbiology and Immunology;
11
Baylor Charles A. Sammons Cancer Center, Dallas, Texas; Texas Oncology, US Oncology, Dallas, Texas;
12
‖‖The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
13
¶Cancer Biology, **Breast Cancer Research Program; Vanderbilt Ingram Cancer Center, Nashville, Tennessee;
14
From the Departments of ‡Medicine, ¶Cancer Biology, **Breast Cancer Research Program; Vanderbilt Ingram Cancer Center, Nashville, Tennessee; carlos.arteaga@vanderbilt.edu.

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.

PMID:
25953087
PMCID:
PMC4587316
DOI:
10.1074/mcp.M115.049783
[Indexed for MEDLINE]
Free PMC Article

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