Tyrosine phosphorylation profiling reveals the signaling network characteristics of Basal breast cancer cells.

Abstract

To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry-based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup.

• Authors: Falko Hochgräfe, Luxi Zhang, Sandra A O'Toole, Brigid C Browne, Mark Pinese, Ana Porta Cubas, Gillian M Lehrbach, David R Croucher, Danny Rickwood, Alice Boulghourjian, Robert Shearer, Radhika Nair, Alexander Swarbrick, Dana Faratian, Peter Mullen, David J Harrison, Andrew V Biankin, Robert L Sutherland, Mark J Raftery, Roger J Daly
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 22 Pg. 9391-401 (Nov 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20861192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 AACR.

Chemical References

• Phosphoproteins
• Protein Kinase Inhibitors
• Tyrosine
• ErbB Receptors
• Proto-Oncogene Proteins c-met
• Focal Adhesion Protein-Tyrosine Kinases
• lyn protein-tyrosine kinase
• src-Family Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cluster Analysis
• ErbB Receptors (genetics, metabolism)
• Female
• Focal Adhesion Protein-Tyrosine Kinases (genetics, metabolism)
• Humans
• Kaplan-Meier Estimate
• Mammary Neoplasms, Experimental (genetics, metabolism, pathology)
• Mice
• Neoplasms, Basal Cell (genetics, metabolism, pathology)
• Phosphoproteins (classification, metabolism)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Proteomics
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• RNA Interference
• Signal Transduction
• Tyrosine (metabolism)
• src-Family Kinases (genetics, metabolism)