This proposal will test the hypothesis that up-regulation of the HEF1 gene in breast tumors is an important contributing factor for cancer metastasis. This is based on the ability of elevated HEF1 to drive proliferation and invasion. For invasion, cells become increasingly motile and acquire the ability to invade surrounding tissue which enables metastasis. A series of studies within the past year have nominated the HEF1 protein as an essential switch for pro-metastatic behavior in tumors. These studies have identified HEF1 as a component of a small "signature" of genes upregulated in metastasizing breast adenocarcinomas, shown HEF1 is important for glioblastoma invasiveness, and determined that upregulation of HEF1 occurred in more than 30% of metastatic melanomas. In this proposal, we will address two basic questions: 1) How does absence or overexpression of HEF1 condition AurA activation, and 2) How does HEF1 regulate invasion in breast cancer cells? In specific experiments to answer these questions, Aim 1 will use mechanistic, cell-based assays to investigate how HEF1 regulates AurA degradation. We will test the hypothesis that HEF1 protects AurA from ubiquitin-dependent proteosome degradation and determine the impact of the HEF1-AurA complex on efficacy of clinically relevant AurA inhibitors.
Aim 2 will define the molecular mechanisms underlying HEF1's invasion promoting abilities. We will test the hypothesis that HEF1-activated AurA activates histone deacetylase HDAC6 and promotes deacetylation of invadopodia seeding component- cortactin.
In Aim 3 we will test the hypothesis that elevated HEF1 expression contributes significantly to breast cancer metastasis using orthotopic mouse xenograft models with inducible shRNAs against HEF1 and modern multimodal non-invasive fluorescent/bioluminescent imaging technology to establish molecular mechanisms of HEF1-driven tumor growth and metastasis in human cancer. The ultimate goal of these experiments is to improve the diagnosis and treatment of cancer in human patients.

Public Health Relevance

Changes in HEF1 protein expression drive metastasis in more than 30% of human melanomas, and have been linked to metastatic behavior in breast cancer. The proposed work will elucidate the action of HEF1 in metastatic cancer progression, and reveal points of cancer cell vulnerability that can be therapeutically exploited. Further, the proposed work will directly test existing, clinically validated drugs targeting AurA and HDAC6 for effects on metastases formation, and may thus provide basis for using these agents as new anti-invasive measures prior to tumor metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148671-05
Application #
8608492
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$265,382
Indirect Cost
$84,234
Name
West Virginia University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
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Addison, Joseph B; Koontz, Colton; Fugett, James H et al. (2015) KAP1 promotes proliferation and metastatic progression of breast cancer cells. Cancer Res 75:344-55
Kozyulina, Polina Y; Loskutov, Yuriy V; Kozyreva, Varvara K et al. (2015) Prometastatic NEDD9 Regulates Individual Cell Migration via Caveolin-1-Dependent Trafficking of Integrins. Mol Cancer Res 13:423-38
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Ice, Ryan J; McLaughlin, Sarah L; Livengood, Ryan H et al. (2013) NEDD9 depletion destabilizes Aurora A kinase and heightens the efficacy of Aurora A inhibitors: implications for treatment of metastatic solid tumors. Cancer Res 73:3168-80
Moore, Finola E; Osmundson, Evan C; Koblinski, Jennifer et al. (2010) The WW-HECT protein Smurf2 interacts with the Docking Protein NEDD9/HEF1 for Aurora A activation. Cell Div 5:22