PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer

Abstract

Aurora A kinase is overexpressed in the majority of breast carcinomas. A chemical genetic approach was used to identify the malignant targets of Aurora A, which revealed pleckstrin-homology-like domain protein PHLDA1 as an Aurora A substrate. PHLDA1 downregulation is a powerful prognostic predictor for breast carcinoma, which was confirmed in our study. We further show that downregulation of PHLDA1 is associated with estrogen receptor (ER) expression in breast carcinoma. Aurora A directly phosphorylates PHLDA1 leading to its degradation. PHLDA1 also negatively regulates Aurora A, thereby triggering a feedback loop. We demonstrate the underlying mechanisms by which PHLDA1 upregulation strongly antagonizes Aurora-A-mediated oncogenic pathways, thereby revealing PHLDA1 degradation as a key mechanism by which Aurora A promotes breast malignancy. Thus, not surprisingly, PHLDA1 upregulation acts synergistically with Aurora A inhibition in promoting cell death. PHLDA1 overexpression might therefore be an alternative method to modulate Aurora A deregulation in breast carcinoma. Finally, this study led to the discovery of a mutation in the Aurora A active site that renders it amenable to the chemical genetic approach. Similar mutations are required for Aurora B, suggesting that this modified approach can be extended to other kinases that have hitherto not been amenable to this methodology.