title: XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway.
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.
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.|Department of Cancer Immunology and AIDS.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.|Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu, Sichuan, China.
authors.forename: Qianzi
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Greenblatt
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases and Institute for Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.|Department of Cancer Immunology and AIDS.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatziapostolou
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elgene
authors.initials: E
authors.lastname: Lim
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Wai Leong
authors.initials: WL
authors.lastname: Tam
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Ni
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215, USA.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Junhua
authors.initials: J
authors.lastname: Mai
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.|Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Dorothy Z
authors.initials: DZ
authors.lastname: Hu
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.
authors.forename: Stanley
authors.initials: S
authors.lastname: Adoro
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Bella
authors.initials: B
authors.lastname: Hu
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.
authors.forename: Minkyung
authors.initials: M
authors.lastname: Song
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.
authors.forename: Chen
authors.initials: C
authors.lastname: Tan
authors.affiliation: Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Landis
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.|Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.|Methodist Cancer Center, Houston, TX 77030, USA.
authors.forename: Jenny C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, MA 02215, USA.|Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D012319:RNA Polymerase II / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D064726:Triple Negative Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D051927:CD24 Antigen; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D012319:RNA Polymerase II