Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization1. 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 tumours4,5,6, 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 options7,8. 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 CD44highCD24low population. Hypoxia-inducing factor 1α (HIF1α) is known to be hyperactivated in TNBCs9,10. 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.
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Gene Expression Omnibus
ChIP-seq and gene expression microarray data have been deposited in the NCBI Gene Expression Omnibus and are accessible through GEO series accession number GSE49955.
We thank W. G. Kaelin, A.-H. Lee, F. Martinon, M. N. Wein and X. Li for critical review of the manuscript. We are grateful to A. L. Richardson, H. Xu and J. Wang for advice and discussions. We thank L. A. Paskett, X. Liu, R. Kim and Y. Liu for technical support. This work was supported by the 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.).
Extended data figures
This file contains a Supplementary Table listing genes of the XBP1 gene signature.
This file contains a Supplementary Table listing the clinical information of TNBC patient cohorts.
This file contains a Supplementary Table listing the ChIP primer sequences used in this study.