Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival.
Mutant Abl kinases (such as BCR-Abl) drive the development of leukemia; however little is known regarding whether Abl kinases contribute to the development or progression of solid tumors. We recently demonstrated that endogenous Abl kinases (c-Abl, Arg) are activated by deregulated ErbB receptors and Src kinases, and drive invasion of aggressive breast cancer cells. In this study, we examined whether activation of endogenous Abl kinases affects transformation, proliferation and survival, which are major contributors to breast cancer development and metastatic progression. Using a pharmacological inhibitor and RNAi, we demonstrate that activation of endogenous Abl kinases dramatically promotes breast cancer cell proliferation and anchorage-independent growth in serum, as well as survival following nutrient deprivation. Activation of Abl kinases mediates phosphorylation of STAT3, and promotes proliferation by accelerating G(1) --> S progression. Moreover, we identify IGF-1R as a novel upstream activator of endogenous Abl kinases, and demonstrate that Abl kinase activation is required for IGF-1-stimulated cell cycle progression in breast cancer cells. Since activation of Abl kinases affects multiple steps of breast cancer development and progression, Abl kinase inhibitors are likely to be effective agents for the treatment of breast cancers containing highly active Abl kinases.
Srinivasan
D
D
Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, KY 40536, USA.
Sims
J T
JT
Plattner
R
R
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D016313:Genes, abl / Q000502:physiology; D006801:Humans; D009361:Neoplasm Invasiveness; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*
D016315:Proto-Oncogene Proteins c-abl