Growth factors modulate cell proliferation, migration, and survival. Precise regulation of these processes is critical as deregulated growth factor signaling increases cellular migration and drives tumor invasion and metastasis, the major cause of cancer-related deaths. Although Abl nonreceptor tyrosine kinases initiate leukemia development, their role in the development or progression of solid tumors has not been studied. Previously, we showed that Abl kinases are activated downstream of growth factor receptors via Src family kinases and PLC-yl, and influence growth factor-mediated cytoskeletal reorganization and migration in fibroblasts. Deregulation of growth factor receptors, Src kinases and PLC-yl in solid tumors, such as breast cancer, drives tumor invasion and metastasis. Our studies demonstrate that the Abl kinases are dramatically activated downstream of activated growth factor receptors and Src kinases in highly aggressive breast cancer cell lines, and promote breast cancer invasion. Based on these findings, the overall objective of this proposal is to characterize the conditions leading to Abl kinase activation in breast cancer, and to define invasion-promoting signaling cascades controlled by the Abl kinases. We hypothesize that Abl family kinases translate and direct growth factor receptor and Src kinase-mediated signals to influence breast cancer invasion and metastasis.
Three Specific Aims are described to evaluate this hypothesis: 1) Determine the conditions that activate the Abl kinases in breast cancer;2) Identify biological and molecular mechanisms by which Abl kinases promote breast cancer cell invasion;and 3) Determine whether activation of the Abl kinases promotes breast cancer metastasis, in vivo. To achieve our goal, we will combine biochemical, molecular, cellular, and whole animal approaches using: 1) primary breast tissue, breast cancer cell lines;RNAi, and inhibitors to identify mechanisms and conditions of Abl activation;2) RNAi, chemotaxis, invasion, and zymography assays to identify mechanisms by which Abl kinases promote invasion;and 3) in vivo metastasis studies to assess whether activation of the Abl kinases promotes metastasis in immune- compromised mice. These data are likely to provide mechanistic insight into how abnormal regulation of the Abl kinases contributes to breast cancer progression, which may aid in the discovery of new drug combinations for preventing breast cancer metastasis and decreasing mortality.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116784-04
Application #
7897809
Study Section
Intercellular Interactions (ICI)
Program Officer
Ault, Grace S
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2010-08-05
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$267,536
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Tripathi, Rakshamani; Fiore, Leann S; Richards, Dana L et al. (2018) Abl and Arg mediate cysteine cathepsin secretion to facilitate melanoma invasion and metastasis. Sci Signal 11:
Zhao, H; Chen, M-S; Lo, Y-H et al. (2014) The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer. Oncogene 33:1429-37
Fiore, Leann S; Ganguly, Sourik S; Sledziona, James et al. (2014) c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer. Oncogene 33:4508-4520
Sims, Jonathan T; Ganguly, Sourik S; Bennett, Holly et al. (2013) Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-?B and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS One 8:e55509
Ganguly, Sourik S; Plattner, Rina (2012) Activation of abl family kinases in solid tumors. Genes Cancer 3:414-25
Ganguly, S S; Fiore, L S; Sims, J T et al. (2012) c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression. Oncogene 31:1804-16
Zhao, Huajun; Ou-Yang, Fu; Chen, I-Fen et al. (2010) Enhanced resistance to tamoxifen by the c-ABL proto-oncogene in breast cancer. Neoplasia 12:214-23
Sims, Jonathan T; Ganguly, Sourik; Fiore, Leann S et al. (2009) STI571 sensitizes breast cancer cells to 5-fluorouracil, cisplatin and camptothecin in a cell type-specific manner. Biochem Pharmacol 78:249-60
Srinivasan, Divyamani; Kaetzel, David M; Plattner, Rina (2009) Reciprocal regulation of Abl and receptor tyrosine kinases. Cell Signal 21:1143-50
Sims, Jonathan T; Plattner, Rina (2009) MTT assays cannot be utilized to study the effects of STI571/Gleevec on the viability of solid tumor cell lines. Cancer Chemother Pharmacol 64:629-33

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