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Nature. 2014 Apr 3;508(7494):103-107. doi: 10.1038/nature13119. Epub 2014 Mar 23.

XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.

Author information

1
Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.
2
Center for Systems Biomedicine, Division of Digestive Diseases and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Department of Cancer Immunology and AIDS.
4
Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
6
Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, China.
7
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
9
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
10
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215, USA.
11
Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
12
Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
13
Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
14
Methodist Cancer Center, Houston, TX 77030, USA.
15
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
#
Contributed equally

Abstract

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.

PMID:
24670641
PMCID:
PMC4105133
DOI:
10.1038/nature13119
[Indexed for MEDLINE]
Free PMC Article

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