Publication Date:
2014-03-29
Description:
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 1alpha (HIF1alpha) 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 HIF1alpha that regulates the expression of HIF1alpha 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 HIF1alpha 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105133/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Xi -- Iliopoulos, Dimitrios -- Zhang, Qing -- Tang, Qianzi -- Greenblatt, Matthew B -- Hatziapostolou, Maria -- Lim, Elgene -- Tam, Wai Leong -- Ni, Min -- Chen, Yiwen -- Mai, Junhua -- Shen, Haifa -- Hu, Dorothy Z -- Adoro, Stanley -- Hu, Bella -- Song, Minkyung -- Tan, Chen -- Landis, Melissa D -- Ferrari, Mauro -- Shin, Sandra J -- Brown, Myles -- Chang, Jenny C -- Liu, X Shirley -- Glimcher, Laurie H -- AI32412/AI/NIAID NIH HHS/ -- CA112663/CA/NCI NIH HHS/ -- K99 CA175290/CA/NCI NIH HHS/ -- K99CA175290/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- R00 CA160351/CA/NCI NIH HHS/ -- R01 AI032412/AI/NIAID NIH HHS/ -- R01 CA112663/CA/NCI NIH HHS/ -- R01 HG004069/HG/NHGRI NIH HHS/ -- R01HG004069/HG/NHGRI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Apr 3;508(7494):103-7. doi: 10.1038/nature13119. Epub 2014 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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, New York 10065, USA. ; 1] Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [3]. ; 1] Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2]. ; 1] Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China [2] Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Ya'an, Sichuan 625014, China [3]. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; 1] Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02215, USA. ; Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA. ; 1] Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA [2] Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA. ; Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Division of Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA. ; Houston Methodist Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA [2] Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA. ; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA. ; 1] Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA [2] Houston Methodist Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670641" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD24/metabolism
;
Antigens, CD44/metabolism
;
Cell Hypoxia/genetics
;
Cell Line, Tumor
;
Cell Proliferation
;
DNA-Binding Proteins/deficiency/genetics/*metabolism
;
Disease Progression
;
Female
;
Gene Expression Regulation, Neoplastic
;
Gene Regulatory Networks
;
Gene Silencing
;
Humans
;
Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
;
Mice
;
Neoplasm Invasiveness
;
Neoplasm Recurrence, Local
;
Prognosis
;
RNA Polymerase II/metabolism
;
Transcription Factors/deficiency/genetics/*metabolism
;
Transcription, Genetic
;
Triple Negative Breast Neoplasms/blood supply/genetics/*metabolism/*pathology
;
Unfolded Protein Response
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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