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: Xi Chen, Dimitrios Iliopoulos, Qing Zhang, Qianzi Tang, Matthew B Greenblatt, Maria Hatziapostolou, Elgene Lim, Wai Leong Tam, Min Ni, Yiwen Chen, Junhua Mai, Haifa Shen, Dorothy Z Hu, Stanley Adoro, Bella Hu, Minkyung Song, Chen Tan, Melissa D Landis, Mauro Ferrari, Sandra J Shin, Myles Brown, Jenny C Chang, X Shirley Liu, Laurie H Glimcher
• Journal: Nature (Nature) Vol. 508 Issue 7494 Pg. 103-107 (Apr 03 2014) ISSN: 1476-4687 [Electronic] England
• PMID: 24670641 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD24 Antigen
• DNA-Binding Proteins
• HIF1A protein, human
• Hyaluronan Receptors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Regulatory Factor X Transcription Factors
• Transcription Factors
• X-Box Binding Protein 1
• XBP1 protein, human
• Xbp1 protein, mouse
• RNA Polymerase II

Topics

• Animals
• CD24 Antigen (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
• Hyaluronan Receptors (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Neoplasm Invasiveness
• Neoplasm Recurrence, Local
• Prognosis
• RNA Polymerase II (metabolism)
• Regulatory Factor X Transcription Factors
• Transcription Factors (deficiency, genetics, metabolism)
• Transcription, Genetic
• Triple Negative Breast Neoplasms (blood supply, genetics, metabolism, pathology)
• Unfolded Protein Response
• X-Box Binding Protein 1