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Volume 28, No 3, Mar 2018

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 28 Issue 3, March 2018: 336-358

ORIGINAL ARTICLES

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

Qiang Wang1,2,*, Jun Jiang3,*, Guoguang Ying4,*, Xiao-Qing Xie1,2,*, Xia Zhang1,2, Wei Xu1,2,5, Xuemin Zhang6, Erwei Song7, Hong Bu8, Yi-Fang Ping1,2, Xiao-Hong Yao1,2, Bin Wang1,2, Shilei Xu4, Ze-Xuan Yan1,2,Yanhong Tai9,10, Baoquan Hu3, Xiaowei Qi3, Yan-Xia Wang1,2, Zhi-Cheng He1,2, Yan Wang1,2, Ji Ming Wang11, You-Hong Cui1,2, Feng Chen12, Kun Meng12, Zhaoyi Wang1,2,13, Xiu-Wu Bian1,2

1 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; 2 Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing 400038, China; 3 Department of Breast Diseases, Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China; 4 Laboratory of Cancer Cell Biology, Tianjin Cancer Institute, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China; 5 McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706, USA; 6 State Key Laboratory of Proteomics, Institute of Basic Medical Sciences, China National Center of Biomedical Analysis, Beijing 100850, China; 7 Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; 8 Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, China; 9 Department of Pathology, General Hospital of PLA, Beijing 100853, China; 10Department of Pathology, No.307 Hospital of PLA, Beijing 100071, China; 11Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; 12Shenogen Pharma Group, Beijing 100085, China; 13Departments of Medical Microbiology & Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA Correspondence: Xiu-Wu Bian, Tel: +86-23-68754431; Fax: +86-23-65397004(bianxiuwu@263.net)

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.


10.1038/cr.2018.15

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