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

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 & 4 others Myles Brown, Jenny C. Chang, X. Shirley Liu, Laurie H. Glimcher

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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.

Original languageEnglish (US)
Pages (from-to)103-107
Number of pages5
JournalNature
Volume508
Issue number1
DOIs
StatePublished - 2014

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Triple Negative Breast Neoplasms
Protein Unfolding
Neoplasms
Breast Neoplasms
Endoplasmic Reticulum Stress
RNA Polymerase II
Gene Regulatory Networks
Chromosome Mapping
Progesterone Receptors
Hypoxia
Transcriptome
Endoplasmic Reticulum
Estrogen Receptors
Breast
Cohort Studies
Epithelial Cells
Recurrence
Cell Line
Therapeutics
Growth

ASJC Scopus subject areas

  • General

Cite this

Chen, X., Iliopoulos, D., Zhang, Q., Tang, Q., Greenblatt, M. B., Hatziapostolou, M., ... Glimcher, L. H. (2014). XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature, 508(1), 103-107. https://doi.org/10.1038/nature13119

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

In: Nature, Vol. 508, No. 1, 2014, p. 103-107.

Research output: Contribution to journalArticle

Chen, X, Iliopoulos, D, Zhang, Q, Tang, Q, Greenblatt, MB, Hatziapostolou, M, Lim, E, Tam, WL, Ni, M, Chen, Y, Mai, J, Shen, H, Hu, DZ, Adoro, S, Hu, B, Song, M, Tan, C, Landis, MD, Ferrari, M, Shin, SJ, Brown, M, Chang, JC, Liu, XS & Glimcher, LH 2014, 'XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway', Nature, vol. 508, no. 1, pp. 103-107. https://doi.org/10.1038/nature13119
Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. Nature. 2014;508(1):103-107. https://doi.org/10.1038/nature13119
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. / XBP1 promotes triple-negative breast cancer by controlling the HIF1α pathway. In: Nature. 2014 ; Vol. 508, No. 1. pp. 103-107.
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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 1{\^I}± (HIF1{\^I}±) 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 HIF1{\^I}± that regulates the expression of HIF1{\^I}± 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 HIF1{\^I}± 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.",
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AU - Hatziapostolou, Maria

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AU - Landis, Melissa D.

AU - Ferrari, Mauro

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AU - Liu, X. Shirley

AU - Glimcher, Laurie H.

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