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Cell Res. 2018 Mar;28(3):336-358. doi: 10.1038/cr.2018.15. Epub 2018 Feb 2.

Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells.

Wang Q1,2, Jiang J3, Ying G4, Xie XQ1,2, Zhang X1,2, Xu W1,2,5, Zhang X6, Song E7, Bu H8, Ping YF1,2, Yao XH1,2, Wang B1,2, Xu S4, Yan ZX1,2, Tai Y9,10, Hu B3, Qi X3, Wang YX1,2, He ZC1,2, Wang Y1,2, Wang JM11, Cui YH1,2, Chen F12, Meng K12, Wang Z1,2,13, Bian XW1,2.

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Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China.
Department of Breast Diseases, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
Laboratory of Cancer Cell Biology, Tianjin Cancer Institute, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA.
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, China National Center of Biomedical Analysis, Beijing 100850, China.
Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Pathology, General Hospital of PLA, Beijing 100853, China.
Department of Pathology, No.307 Hospital of PLA, Beijing 100071, China.
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
Shenogen Pharma Group, Beijing 100085, China.
Departments of Medical Microbiology & Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA.


The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer.

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