AurA kinase expression is linked to human disease since the extent of AurA up-regulation was significantly associated with advanced tumor stage and the occurrence of metastasis. AurA inhibitors have recently entered phase II clinical trials for cancer treatment, but application of these inhibitors for treatment of advanced human cancers has demonstrated limited efficacy. The reasons why potent in vitro inhibitors of AurA are inefficient under these conditions are unknown. In our current study, we define the mechanisms by which AurA is upregulated in breast tumor cells and what impact HEF1 expression has on AurA-associated occurrence of metastasis. Our hypothesis is that over-expression of HEF1 protein in breast cancer cells will protect AurA from proteolytic degradation, resulting in activation of AurA kinase. Here we demonstrate that direct binding of HEF1 stabilizes AurA by blocking the cdh1 binding site and limiting AurA ubiquitination. HEF1 binding decreases the efficacy of AurA inhibitors in cell culture. Deletion of HEF1 by gene knockout and depletion by siRNA in cell lines cause dramatic decreases in AurA protein level and kinase activity - indicating HEF1 is the major AurA regulator in vivo. We further show that deletion of HEF1 reduces tumor cell proliferation and invasion in mouse mammary tumor models. These data provide insights into the potential development of small molecule inhibitors that could be used therapeutically to target the HEF1/AurA pathway and thereby inhibit tumor formation.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1086.