XBP1 Promotes Triple Negative Breast Cancer By Controlling the HIF1 α Pathway

By Xi Chen, Dimitrios Iliopoulos, Qing Zhang, Qianzi Tang, M. Greenblatt, M. Hatziapostolou, E. Lim, W. Tam, M. Ni, Yiwen Chen and 14 more. Nature, 2014

791 citations recorded by the source corpus.

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 CD44highCD24low 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.

Subfields: Cell Biology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/062c964625740f2a15d534d813dcf55e556480cc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

In Immunology

In Molecular Biology

Citations in the corpus

ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis (2015, background): “We recently demonstrated that XBP1 facilitates triple-negative breast cancer progression by promoting tumor cell survival and metastatic capacity under hypoxic conditions (Chen et al., 2014).”
Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge (2019, background): “A recent publication has even suggested HIF-1 and hypoxia as hallmarks of TNBC [111,112].”
The Unfolded Protein Response and Cell Fate Control. (2017, positive): “XBP1u turnover is mediated in part by the generation of a type II transmembrane domain, allowing its degradation by the ERAD pathway and processing by the signal peptide peptidase (SPP) (Chen et al., 2014a).”
Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer (2017, positive): “Silencing XBP1 potently inhibited mammosphere growth in multiple TNBC cell lines and primary patient samples (Chen et al., 2014).”