机构：[1]Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA[2]Department of Medicine, Weill Cornell Medical College, 1300 York Avenue,New York,NewYork 10065, USA[3]Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA[4]Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA[5]Lineberger Comprehensive Cancer Center, Department of Pathology and LaboratoryMedicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA[6]Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092,China[7]Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Ya’an, Sichuan 625014, China[8]Department of Pathology, Brigham andWomen’s Hospital, Boston, Massachusetts 02115, USA[9]Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts02115, USA[10]Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA[11]Department of Biostatistics and Computational Biology, Dana-Farber CancerInstitute and Harvard School of Public Health, Boston, Massachusetts 02215, USA[12]Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA[13]Department ofCell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA[14]Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA[15]Division of Hematology/Oncology, Children’s Hospital Boston, Boston, Massachusetts 02115, USA[16]Houston Methodist Cancer Center, Houston, Texas 77030, USA[17]Department of Pathology andLaboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA
Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization. One such adaptive pathway is the unfolded protein (UPR) or endoplasmic reticulum (ER) stress response mediated in part by the ER-localized transmembrane sensor IRE1 (ref. 2) and its substrate XBP1 (ref. 3). Previous studies report UPR activation in various human tumours, but the role of XBP1 in cancer progression in mammary epithelial cells is largely unknown. Triple-negative breast cancer (TNBC)--a form of breast cancer in which tumour cells do not express the genes for oestrogen receptor, progesterone receptor and HER2 (also called ERBB2 or NEU)--is a highly aggressive malignancy with limited treatment options. Here we report that XBP1 is activated in TNBC and has a pivotal role in the tumorigenicity and progression of this human breast cancer subtype. In breast cancer cell line models, depletion of XBP1 inhibited tumour growth and tumour relapse and reduced the CD44(high)CD24(low) population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs. Genome-wide mapping of the XBP1 transcriptional regulatory network revealed that XBP1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that regulates the expression of HIF1α targets via the recruitment of RNA polymerase II. Analysis of independent cohorts of patients with TNBC revealed a specific XBP1 gene expression signature that was highly correlated with HIF1α and hypoxia-driven signatures and that strongly associated with poor prognosis. Our findings reveal a key function for the XBP1 branch of the UPR in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.
基金：
National Institutes of Health
(CA112663 and AI32412 to L.H.G.; R01HG004069 to X.S.L.; K99CA175290 to Y.C.),
the Leukemia and Lymphoma Society (to X.C.) and the National Natural Science
Foundation of China (NSFC31329003 to X.S.L.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2014]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2025]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA[2]Department of Medicine, Weill Cornell Medical College, 1300 York Avenue,New York,NewYork 10065, USA
通讯作者：
通讯机构：[1]Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA[2]Department of Medicine, Weill Cornell Medical College, 1300 York Avenue,New York,NewYork 10065, USA
推荐引用方式(GB/T 7714)：
Xi Chen,Dimitrios Iliopoulos,Qing Zhang,et al.XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.[J].Nature.2014,508(7494):103-107.doi:10.1038/nature13119.
APA：
Xi Chen,Dimitrios Iliopoulos,Qing Zhang,Qianzi Tang,MatthewB. Greenblatt...&Laurie H. Glimcher.(2014).XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway..Nature,508,(7494)
MLA：
Xi Chen,et al."XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.".Nature 508..7494(2014):103-107
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