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.
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.
|Kozyreva, Varvara K; Kiseleva, Anna A; Ice, Ryan J et al. (2016) Combination of Eribulin and Aurora A Inhibitor MLN8237 Prevents Metastatic Colonization and Induces Cytotoxic Autophagy in Breast Cancer. Mol Cancer Ther 15:1809-22|
|Iida, Joji; Dorchak, Jesse; Clancy, Rebecca et al. (2015) Role for chondroitin sulfate glycosaminoglycan in NEDD9-mediated breast cancer cell growth. Exp Cell Res 330:358-70|
|Loskutov, Y V; Kozyulina, P Y; Kozyreva, V K et al. (2015) NEDD9/Arf6-dependent endocytic trafficking of matrix metalloproteinase 14: a novel mechanism for blocking mesenchymal cell invasion and metastasis of breast cancer. Oncogene 34:3662-75|
|Park, Jino; Schlederer, Michaela; Schreiber, Martin et al. (2015) AF1q is a novel TCF7 co-factor which activates CD44 and promotes breast cancer metastasis. Oncotarget 6:20697-710|
|Lin, C-C; Sharma, S B; Farrugia, M K et al. (2015) Kruppel-like factor 4 signals through microRNA-206 to promote tumor initiation and cell survival. Oncogenesis 4:e155|
|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|
|McLaughlin, Sarah L; Ice, Ryan J; Rajulapati, Anuradha et al. (2014) NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis. Mol Cancer Res 12:69-81|
|Kozyreva, Varvara K; McLaughlin, Sarah L; Livengood, Ryan H et al. (2014) NEDD9 regulates actin dynamics through cortactin deacetylation in an AURKA/HDAC6-dependent manner. Mol Cancer Res 12:681-93|
|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|
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