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Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ER? in breast cancer.


ABSTRACT: 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 oestrogen receptor (ER)?. Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ER?-positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ER?-positive tumours. 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 ER? on serine-167 and -305, leading to increase in ER? DNA-binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with disease-free survival in ER?-positive but not ER?-negative breast cancers. These data suggest that Aurora-A has a pivotal role in tamoxifen resistance and ER? is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a prognostic marker in ER?-positive tumour and a critical therapeutic target in tamoxifen-resistant breast cancer, and Aurora-A inhibitor could be used as either an independent or concurrent agent in tamoxifen-resistant tumour.

SUBMITTER: Zheng XQ 

PROVIDER: S-EPMC4002670 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer.

Zheng X Q XQ   Guo J P JP   Yang H H   Kanai M M   He L L LL   Li Y Y YY   Koomen J M JM   Minton S S   Gao M M   Ren X B XB   Coppola D D   Cheng J Q JQ  

Oncogene 20131028 42


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 oestrogen receptor (ER)α. Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ERα-positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ERα-positive tumours. Notably, Aurora-A inhibitor MLN8237, which is currently in clinical trial,  ...[more]

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