Hypoxic stimuli promote tumor cell survival, angiogenesis and breast cancer invasion. The expression of vascular endothelial growth factor (VEGF) requires hypoxia-induced transcription, mRNA stability, mRNA shuttling, protein translation and secretion. Secreted VEGF promotes local vascular permeability and angiogenesis, thus promoting tumor expansion and metastatic potential. We have identified two essential mechanisms that contribute to hypoxia-dependent VEGF expression: 1) post-transcriptional control of mRNA processing by double-stranded RNA-binding proteins, DRBP76 and ILF3, and 2) AMP-activated protein kinase a2 (AMPKa2) control of mRNA shuttling and translation. The central theme for this proposal is that tumor progression in hypoxic microenvironments requires AMPK signaling for VEGF expression and adaptive cell survival via post-transcriptional mechanisms and modulation of growth factor signaling pathways. Hypoxia-induced AMPK also represses mitogen activated protein kinase (MAPK) pathways in breast cancer cells, suggesting that systemic AMPK activation could repress breast cancer proliferation in vivo. These hypotheses will be tested in the following aims:
Specific Aim 1 will define the role of double stranded RNA-binding proteins (DRBP76/ILF3) in hypoxia-induced VEGF mRNA stability, intracellular shuttling and translation and for biological relevance in experimental models of breast tumor progression, angiogenesis and metastasis.
Specific Aim 2 will investigate the role of AMPKa2 isoform and AMPK signaling in controlling DRBP/ILF3 function in hypoxia-induced VEGF expression via post-transcriptional mechanisms and repression of MAPK signaling in breast cancer cells. Specific Am 3 will assess the role of AMPKa2 as a central regulator of human breast cancer progression, requirement for endogenous tumorigenesis and the potential for systemic AMPK activation as a novel therapeutic intervention for primary and metastatic breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064436-14
Application #
7893851
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
1995-04-05
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
14
Fiscal Year
2010
Total Cost
$271,728
Indirect Cost
Name
University of Connecticut
Department
Biology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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