Subjects

Abstract

Cancer cells induce a set of adaptive response pathways to survive in the face of stressors due to inadequate vascularization1. 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 tumours4,5,6, 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 options7,8. 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 TNBCs9,10. 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

ChIP-seq and gene expression microarray data have been deposited in the NCBI Gene Expression Omnibus and are accessible through GEO series accession number GSE49955.

References

  1. 1.

    & Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)

  2. 2.

    & The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011)

  3. 3.

    , , , & XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891 (2001)

  4. 4.

    et al. The differentiation and stress response factor XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 11, 349–360 (2007)

  5. 5.

    et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 20, 400–413 (2011)

  6. 6.

    et al. Virus-tumor interactome screen reveals ER stress response can reprogram resistant cancers for oncolytic virus-triggered caspase-2 cell death. Cancer Cell 20, 443–456 (2011)

  7. 7.

    , , , & Triple-negative breast cancer: disease entity or title of convenience? Nature Rev. Clin. Oncol. 7, 683–692 (2010)

  8. 8.

    , & Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948 (2010)

  9. 9.

    et al. SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 487, 380–384 (2012)

  10. 10.

    Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012)

  11. 11.

    et al. CD44+/CD24−/low cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum. Pathol. 43, 364–373 (2012)

  12. 12.

    , , , & CD44+/CD24 phenotype contributes to malignant relapse following surgical resection and chemotherapy in patients with invasive ductal carcinoma. J. Exp. Clin. Cancer Res. 31, 59 (2012)

  13. 13.

    et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl Acad. Sci. USA 106, 13820–13825 (2009)

  14. 14.

    , & An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009)

  15. 15.

    , , & Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc. Natl Acad. Sci. USA 108, 1397–1402 (2011)

  16. 16.

    et al. Hypoxia inducible factor-1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer. Breast Cancer Res. 14, R6 (2012)

  17. 17.

    et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl Acad. Sci. USA 109, 2784–2789 (2012)

  18. 18.

    et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nature Cell Biol. 10, 295–305 (2008)

  19. 19.

    & Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nature Rev. Cancer 8, 851–864 (2008)

  20. 20.

    et al. Imaging the unfolded protein response in primary tumors reveals microenvironments with metabolic variations that predict tumor growth. Cancer Res. 70, 78–88 (2011)

  21. 21.

    et al. A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res. 13, R97 (2011)

  22. 22.

    A New Test for 2×2 Tables. Nature 156, 177 (1945)

  23. 23.

    Significance Tests for 2×2 Tables. Biometrika 34, 123–138 (1947)

  24. 24.

    et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10, 515–527 (2006)

  25. 25.

    et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106–1117 (2008)

  26. 26.

    , , & Measuring reproducibility of high-throughput experiments. Ann. Appl. Stat. 5, 1752–1779 (2011)

  27. 27.

    et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007)

  28. 28.

    et al. A comprehensive view of nuclear receptor cancer cistromes. Cancer Res. 71, 6940–6947 (2011)

  29. 29.

    et al. The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24 stem cell-like breast cancer cells in human tumors. J. Clin. Invest. 121, 2723–2735 (2011)

  30. 30.

    et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365, 671–679 (2005)

Download references

Acknowledgements

We thank W. G. Kaelin, A.-H. Lee, F. Martinon, M. N. Wein and X. Li for critical review of the manuscript. We are grateful to A. L. Richardson, H. Xu and J. Wang for advice and discussions. We thank L. A. Paskett, X. Liu, R. Kim and Y. Liu for technical support. This work was supported by the National Institutes of Health (CA112663 and AI32412 to L.H.G.; R01HG004069 to X.S.L.; K99CA175290 to Y.C.), the Leukemia and Lymphoma Society (to X.C.) and the National Natural Science Foundation of China (NSFC31329003 to X.S.L.).

Author information

Author notes

    • Dimitrios Iliopoulos
    • , Qing Zhang
    •  & Qianzi Tang

    These authors contributed equally to this work.

Affiliations

  1. Sandra and Edward Meyer Cancer Center of Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA

    • Xi Chen
    • , Stanley Adoro
    • , Minkyung Song
    • , Chen Tan
    •  & Laurie H. Glimcher
  2. Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA

    • Xi Chen
    • , Stanley Adoro
    • , Minkyung Song
    • , Chen Tan
    • , Mauro Ferrari
    • , Jenny C. Chang
    •  & Laurie H. Glimcher
  3. Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA

    • Dimitrios Iliopoulos
    •  & Maria Hatziapostolou
  4. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Dimitrios Iliopoulos
    •  & Maria Hatziapostolou
  5. Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Qing Zhang
  6. Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai 200092, China

    • Qianzi Tang
  7. Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Ya’an, Sichuan 625014, China

    • Qianzi Tang
  8. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

    • Matthew B. Greenblatt
  9. Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Elgene Lim
    • , Min Ni
    •  & Myles Brown
  10. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Wai Leong Tam
  11. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts 02215, USA

    • Yiwen Chen
    •  & X. Shirley Liu
  12. Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA

    • Junhua Mai
    • , Haifa Shen
    •  & Mauro Ferrari
  13. Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA

    • Haifa Shen
  14. Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Dorothy Z. Hu
  15. Division of Hematology/Oncology, Children’s Hospital Boston, Boston, Massachusetts 02115, USA

    • Bella Hu
  16. Houston Methodist Cancer Center, Houston, Texas 77030, USA

    • Melissa D. Landis
    •  & Jenny C. Chang
  17. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA

    • Sandra J. Shin

Authors

  1. Search for Xi Chen in:

  2. Search for Dimitrios Iliopoulos in:

  3. Search for Qing Zhang in:

  4. Search for Qianzi Tang in:

  5. Search for Matthew B. Greenblatt in:

  6. Search for Maria Hatziapostolou in:

  7. Search for Elgene Lim in:

  8. Search for Wai Leong Tam in:

  9. Search for Min Ni in:

  10. Search for Yiwen Chen in:

  11. Search for Junhua Mai in:

  12. Search for Haifa Shen in:

  13. Search for Dorothy Z. Hu in:

  14. Search for Stanley Adoro in:

  15. Search for Bella Hu in:

  16. Search for Minkyung Song in:

  17. Search for Chen Tan in:

  18. Search for Melissa D. Landis in:

  19. Search for Mauro Ferrari in:

  20. Search for Sandra J. Shin in:

  21. Search for Myles Brown in:

  22. Search for Jenny C. Chang in:

  23. Search for X. Shirley Liu in:

  24. Search for Laurie H. Glimcher in:

Contributions

X.C. and L.H.G. designed the research; X.C., D.I., Q.Z., M.B.G., M.H., E.L., D.Z.H., S.A., B.H., C.T. and M.S. did the experiments; Q.T. and Y.C. performed the bioinformatics analysis; X.S.L. supervised the bioinformatics analysis; M.N., W.L.T., M.B. and S.J.S. contributed to discussions and critical reagents; J.C.C., M.F., M.D.L., H.S. and J.M. contributed to the patient-derived xenograft experiments; X.C. and L.H.G wrote the paper.

Competing interests

L.H.G. holds equity in and is on the corporate board of directors of Bristol-Myers Squibb.

Corresponding author

Correspondence to Laurie H. Glimcher.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This file contains a Supplementary Table listing genes of the XBP1 gene signature.

  2. 2.

    Supplementary Table 2

    This file contains a Supplementary Table listing the clinical information of TNBC patient cohorts.

  3. 3.

    Supplementary Table 3

    This file contains a Supplementary Table listing the ChIP primer sequences used in this study.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature13119

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.