HEF1/NEDD9 is a cytoplasmic adaptor protein and a well-established marker of poor prognosis in different cancers with invasive tumor signature. We have previously reported that NEDD9 regulates stability and activation of mitotic kinase AurA/AURKA leading to phosphorylation of multiple cytoplasmic substrates, such as HDAC6, Src, CTTN, Arp/C and cofilin involved in migration and invasion. Our novel findings indicate that decrease in NEDD9 expression in TNBCs leads to translocation of AURKA to the nucleus. Presence of nuclear AURKA correlates with increase in metastatic colonization and sensitivity to AURKA inhibitors, but molecular mechanisms of this phenomenon and its role in tumor progression and metastasis is currently unknown. Interestingly, depletion of NEDD9 in HER2+ cancers decreases metastasis, thus suggesting differential role of NEDD9 in HER2+ BCs. Our novel findings indicate that NEDD9 emerges as a critical regulator of proliferation and sensitivity of HER2+ breast cancers to Herceptin via regulation of HER2 trafficking/recycling. The objective of this application is to determine the role of nuclear AURKA in metastasis in TN and HER2+ breast cancers using characterized cell lines, patient-derived xenografts and a conditional NEDD9 knock-in mouse model. Our central hypothesis is that NEDD9 is required for retention of AURKA in the cytoplasm to promote migration/invasion of tumor cells and a decrease in NEDD9 leads to nuclear translocation of AURKA, thus promoting cell survival in the metastatic niche of TNBCs. Furthermore, upregulation of NEDD9 in HER2+ BCs will lead to an increase in tumor incidence and disease progression. We will test this hypothesis by execution of the following aims:
AIM 1. Determine the role of NEDD9 in AURKA cytoplasmic/nuclear translocation and the impact of nuclear AURKA on metastasis. Our hypothesis is that nuclear AURKA promotes survival and resistance to apoptosis, through the inactivation TFEB and activation of NUPR1 and Sox2 pathways.
AIM 2. Elucidate the role and mechanisms by which overexpression of NEDD9 promotes HER2+ breast cancer using genetically modified mouse models and patient derived xenografts. Our hypothesis is that overexpression of NEDD9 heightens HER2-driven tumorigenesis and confers Herceptin resistance via upregulation of HER2 protein and recycling via late endosomes.
Despite significant progress in treatment options, the cure for metastatic breast cancer still remains elusive. Therefore, it is clear that novel treatment strategies based on the specific pathobiology and sensitivity of metastases are required. The successful completion of this work will lead to significant changes in the clinical strategy to tret metastases through the identification of patients who will mostly benefit from the application of selective anti-AURKA/NEDD9-downstream targets based therapies for triple negative and HER2+ amplified breast cancers; and furthermore, will provide the knowledge to potentially eliminate breast cancer mortality due to metastases.
|Loskutov, Yuriy V; Griffin, Caryn L; Marinak, Kristina M et al. (2018) LPA signaling is regulated through the primary cilium: a novel target in glioblastoma. Oncogene 37:1457-1471|
|Jones, Brandon C; Kelley, Laura C; Loskutov, Yuriy V et al. (2017) Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior. Mol Cancer Res 15:670-682|
|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|
|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|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 19 publications