Abstract
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 G1 → 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.
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Acknowledgements
We thank Jennifer Strange and Greg Bauman for assistance with FACS, Dr Lawrence Brewer for assistance with statistics and Drs Natasha Kyprianou, Vivek Rangnekar and Sayan Mitra for critically reading the manuscript. This work was supported by a Concern Foundation Young Investigator Award, American Cancer Society Institutional Pilot Grant 85-001-16 IRG, and NIH P20 RR20171 from the National Center for Research Resources to RP. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
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Srinivasan, D., Sims, J. & Plattner, R. Aggressive breast cancer cells are dependent on activated Abl kinases for proliferation, anchorage-independent growth and survival. Oncogene 27, 1095–1105 (2008). https://doi.org/10.1038/sj.onc.1210714
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DOI: https://doi.org/10.1038/sj.onc.1210714
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