title: Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα 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)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.
authors.affiliation: 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.
authors.forename: X Q
authors.initials: XQ
authors.lastname: Zheng
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Guo
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: He
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Koomen
authors.affiliation: Departments of Women's Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Minton
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: X B
authors.initials: XB
authors.lastname: Ren
authors.affiliation: Departments of Women's Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: J Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000502:physiology*; D001381:Azepines / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008819:Mice, Nude; D010766:Phosphorylation; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D011743:Pyrimidines / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology*; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001381:Azepines; C530104:CCND1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C550258:MLN 8237; D011743:Pyrimidines; D013629:Tamoxifen; D019938:Cyclin D1; C576917:AURKA protein, human; D064096:Aurora Kinase A