Brachyury promotes tamoxifen resistance in breast cancer by targeting SIRT1.
Tamoxifen is effective for treating estrogen receptor-alpha (ERα)-positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. In the present study, we determine the underlying roles of Brachyury in tamoxifen resistance. Loss- and gain-of-function assay are utilized to confirm the oncogenic roles of Brachyury in breast cancer. Compared with the normal MCF10A cells, Brachyury is commonly overexpressed in breast cancer cell lines. Knockdown of Brachyury inhibits tamoxifen resistance, whereas overexpression of Brachyury enhances tamoxifen resistance as demonstrated increased cell viability and reduced cell apoptosis. Mechanistically, we demonstrate for the first time that Brachyury mediates tamoxifen resistance by regulating Sirtuin-1 (SIRT1). Collectively, our data, as a proof of principle, indicate that Brachyury is a candidate marker for predicting the clinical efficacy of tamoxifen and targeting SIRT1 could overcome resistance to tamoxifen in breast cancer cells.
Department of Oncology, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai 200433, PR China.
Kaichun
K
Li
Department of Oncology, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai 200433, PR China.
Mingzhen
M
Ying
Department of Oncology, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai 200433, PR China.
Dan
D
Feng
Department of Oncology, Tianyou Hospital Affiliated to Tongji University, Shanghai 200331, PR China.
Jie
J
Du
Department of Oncology, Tianyou Hospital Affiliated to Tongji University, Shanghai 200331, PR China.
Shiyu
S
Chen
Department of Oncology, Tianyou Hospital Affiliated to Tongji University, Shanghai 200331, PR China.
Bing
B
Dan
Department of Oncology, Tianyou Hospital Affiliated to Tongji University, Shanghai 200331, PR China.
Cuihua
C
Wang
Department of Oncology, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai 200433, PR China. Electronic address: shtumor@163.com.
Yajie
Y
Wang
D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D005326:Fetal Proteins / Q000096:biosynthesis* / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D061986:MCF-7 Cells; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology*; D000098908:Brachyury Protein
D014408:Biomarkers, Tumor; D005326:Fetal Proteins; D056564:Sirtuin 1; D020825:T-Box Domain Proteins; D013629:Tamoxifen; D000098908:Brachyury Protein; C447939:SIRT1 protein, human
Brachyury; Breast cancer; SIRT1; Tamoxifen resistance