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Oncogene. 2014 Oct 16;33(42):4985-96. doi: 10.1038/onc.2013.444. Epub 2013 Oct 28.

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

Author information

1
1] Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA [2] Departments of Thyroid and Neck Tumour, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of cancer prevention and therapy, National Clinical Research Center of Cancer, Tianjin, PR China [3] Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of cancer prevention and therapy, National Clinical Research Center of Cancer, Tianjin, PR China.
2
Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
3
Departments of Women's Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
4
Departments of Thyroid and Neck Tumour, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of cancer prevention and therapy, National Clinical Research Center of Cancer, Tianjin, PR China.
5
Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Oncology Key Laboratory of cancer prevention and therapy, National Clinical Research Center of Cancer, Tianjin, PR China.
6
Departments of Women's Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

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)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, synergizes with tamoxifen and overcomes tamoxifen resistance. Furthermore, Aurora-A interacts with and phosphorylates ERα on serine-167 and -305, leading to increase in ERα DNA-binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with disease-free survival in ERα-positive but not ERα-negative breast cancers. These data suggest that Aurora-A has a pivotal role in tamoxifen resistance and ERα is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a prognostic marker in ERα-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.

PMID:
24166501
PMCID:
PMC4002670
DOI:
10.1038/onc.2013.444
[Indexed for MEDLINE]
Free PMC Article

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