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Tyrosine phosphorylation profiling reveals the signaling network characteristics of Basal breast cancer cells.
- Source :
-
Cancer research [Cancer Res] 2010 Nov 15; Vol. 70 (22), pp. 9391-401. Date of Electronic Publication: 2010 Sep 21. - Publication Year :
- 2010
-
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.<br /> (Copyright © 2010 AACR.)
- Subjects :
- Animals
Apoptosis drug effects
Blotting, Western
Breast Neoplasms genetics
Breast Neoplasms pathology
Cell Line, Tumor
Cell Proliferation drug effects
Cluster Analysis
ErbB Receptors genetics
ErbB Receptors metabolism
Female
Focal Adhesion Protein-Tyrosine Kinases genetics
Focal Adhesion Protein-Tyrosine Kinases metabolism
Humans
Kaplan-Meier Estimate
Mammary Neoplasms, Experimental genetics
Mammary Neoplasms, Experimental metabolism
Mammary Neoplasms, Experimental pathology
Mice
Neoplasms, Basal Cell genetics
Neoplasms, Basal Cell pathology
Phosphoproteins classification
Phosphoproteins metabolism
Phosphorylation
Protein Kinase Inhibitors pharmacology
Proteomics
Proto-Oncogene Proteins c-met genetics
Proto-Oncogene Proteins c-met metabolism
RNA Interference
src-Family Kinases genetics
src-Family Kinases metabolism
Breast Neoplasms metabolism
Neoplasms, Basal Cell metabolism
Signal Transduction
Tyrosine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 70
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 20861192
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-10-0911