Aurora-A Determines Tamoxifen Sensitivity Through Phosphorylation Of ERa In Breast Cancer

Despite the clinical success of tamoxifen, its resistance remains a major challenge in breast cancer. Here we show that Aurora-A determines tamoxifen sensitivity by regulation of estrogen receptor (ERa). Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ERa positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ERa positive tumors. Notably, Aurora-A inhibitor MLN8237, which is currently in clinical trial, synergizes with tamoxifen and overcomes tamoxifen-resistance. Furthermore, Aurora-A interacts with and phosphorylates ERa on serine-167and-305, leading to increase in ERa DNA-binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with recurrence-free survival in ERa positive but not negative breast cancers. These data suggest that Aurora-A plays a pivotal role in tamoxifen resistance and ERa is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a critical therapeutic target in tamoxifen-resistant breast cancer.ERa positive breast cancer patients are commonly treated with the anti-estrogen tamoxifen, which gives approximately50%reduction in recurrence. Thus, identification of the molecule that causes tamoxifen resistance could considerably improve breast cancer treatment. We show that Aurora-A is a determinant of tamoxifen resistance through phosphoryation of ERa and that Aurora-A inhibitor synergizes with tamoxifen and overcomes tamoxifen resistance in vitro and in vivo. In addition, Aurora-A expression is associated with recurrence-free survival only in ERa positive tumor. These findings reveal Aurora-A as a key player in tamoxifien resistance and small molecule inhibitors of Aurora-A as promising therapeutic agents for tamoxifen-resistance/ERα positive breast cancer.