Abstract 4863: Aurora-A kinase: a nuclear driver of metastasis
| Autor: | Matthew B. Smolkin, Elena N. Pugacheva, Kristina M. Marinak, Yuriy Loskutov, Anna A. Kiseleva |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:4863-4863 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2017-4863 |
| Popis: | Aurora-A Kinase (AURKA) is a serine/threonine kinase that is critical for mitosis. AURKA is overexpressed in 96% of human cancers, including breast cancer. It has been previously shown that AURKA localizes to the nucleus in breast cancer metastases and especially in metastases of Triple Negative Breast Cancer (TNBC). Our objective is to define the role of nuclear AURKA in breast cancer metastasis in TNBC. Here we report that TNBC cells vary in amount of nuclear AURKA and this potentially correlates with their metastatic capabilities. Based on our preliminary findings we hypothesized that nuclear AURKA promotes cell survival and resistance to apoptosis in the metastatic niche. To test this hypothesis we created TNBC cell lines with CRISPR/Cas9 based deletion of endogenous AURKA. We also constructed exogenous AURKA specifically targeted to the nucleus by addition of a nuclear localization signal (NLS) or cytoplasm via addition of a nuclear exclusion signal (NES), respectively. To allow for in vitro and in vivo rescue experiments with exogenous NES or NLS AURKA in sgAURKA expressing TNBC cells, we introduced several silent mutations to avoid sgAURKA targeting. In our pilot orthotopic xenograft study with MDA-MB-231-luc2-Cas9 (TNBC) cells expressing sgAURKA with WT AURKA, NLS-AURKA or AURKA-NES shows a trend of increased metastatic colonization in the AURKA-NLS group. Overall, our results indicate that the amount of nuclear AURKA is increased in metastatic breast cancer cell lines and metastases of TNBC, but the mechanism of this translocation is currently unknown. Elucidation of this mechanism is critical for development of new therapeutical strategies for control and eradication of metastatic disease. Citation Format: Kristina Marinak, Anna Kiseleva, Yuriy Loskutov, Matthew Smolkin, Elena Pugacheva. Aurora-A kinase: a nuclear driver of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4863. doi:10.1158/1538-7445.AM2017-4863 |
| Databáze: | OpenAIRE |
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