Home LiteratureArticle Details
PMID: 25587023 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype.

Oncotarget ·Vol. 5 ·No. 24 ·2014-12-30 ·Pages 12509-27

Xiang L, Gilkes DM, Hu H, Takano N, Luo W, Lu H, Bullen JW, Samanta D, Liang H, Semenza GL

Abstract

Intratumoral hypoxia, which is associated with breast cancer metastasis and patient mortality, increases the percentage of breast cancer stem cells (BCSCs) but the underlying molecular mechanisms have not been delineated. Here we report that hypoxia-inducible factor 1 (HIF-1) triggers the expression and activity of TAZ, a transcriptional co-activator that is required for BCSC maintenance, through two discrete mechanisms. First, HIF-1 binds directly to the WWTR1 gene and activates transcription of TAZ mRNA. Second, HIF-1 activates transcription of the SIAH1 gene, which encodes a ubiquitin protein ligase that is required for the hypoxia-induced ubiquitination and proteasome-dependent degradation of LATS2, a kinase that inhibits the nuclear localization of TAZ. Inhibition of HIF-1α, TAZ, or SIAH1 expression by short hairpin RNA blocked the enrichment of BCSCs in response to hypoxia. Human breast cancer database analysis revealed that increased expression (greater than the median) of both TAZ and HIF-1 target genes, but neither one alone, is associated with significantly increased patient mortality. Taken together, these results establish a molecular mechanism for induction of the BCSC phenotype in response to hypoxia.

MeSH Terms
Acyltransferases Animals Breast Neoplasms/pathology Cell Nucleus/metabolism Female Heterografts Humans Hypoxia-Inducible Factor 1/metabolism MCF-7 Cells Mice Mice, SCID Neoplasm Metastasis Neoplastic Stem Cells/pathology Phenotype Protein Serine-Threonine Kinases/genetics,metabolism Signal Transduction Transcription Factors/biosynthesis,genetics,metabolism Transfection Tumor Suppressor Proteins/genetics,metabolism
Chemicals
Hypoxia-Inducible Factor 1 Transcription Factors Tumor Suppressor Proteins Acyltransferases TAFAZZIN protein, human LATS2 protein, human Protein Serine-Threonine Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Xiang Lisha
Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China. Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Gilkes Daniele M
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Hu Hongxia
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Takano Naoharu
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan.
Luo Weibo
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Lu Haiquan
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Bullen John W
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Samanta Debangshu
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Liang Houjie
Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
Semenza Gregg L
Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD.
References (58)
58 references, click to expand
  1. Overexpression of hypoxia-inducible factor 1alpha is associated with an unfavorable prognosis in lymph node-positive breast cancer.
    Clin Cancer Res. 2002 Jun;8(6):1831-7 PMID: 12060624
  2. Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.
    Clin Cancer Res. 2007 Jun 1;13(11):3207-14 PMID: 17545524
  3. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.
    BMC Genomics. 2008;9:239 PMID: 18498629
  4. The humoral immune system has a key prognostic impact in node-negative breast cancer.
    Cancer Res. 2008 Jul 1;68(13):5405-13 PMID: 18593943
  5. Hypoxia-inducible factor 1alpha is closely linked to an aggressive phenotype in breast cancer.
    Breast Cancer Res Treat. 2008 Aug;110(3):465-75 PMID: 17805961
  6. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome.
    Cell Stem Cell. 2007 Nov;1(5):555-67 PMID: 18371393
  7. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature.
    Cancer Res. 2009 Feb 15;69(4):1302-13 PMID: 19190339
  8. TEAD transcription factors mediate the function of TAZ in cell growth and epithelial-mesenchymal transition.
    J Biol Chem. 2009 May 15;284(20):13355-62 PMID: 19324877
  9. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.
    Cancer Cell. 2009 Jun 2;15(6):501-13 PMID: 19477429
  10. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery.
    PLoS One. 2009;4(7):e6146 PMID: 19582160
  11. Hypoxia and TGF-beta drive breast cancer bone metastases through parallel signaling pathways in tumor cells and the bone microenvironment.
    PLoS One. 2009;4(9):e6896 PMID: 19727403
  12. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.
    Oncogene. 2010 Feb 4;29(5):625-34 PMID: 19946328
  13. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer.
    Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10208-13 PMID: 20479250
  14. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.
    Cell Stem Cell. 2010 Sep 3;7(3):391-402 PMID: 20804974
  15. The hippo signaling pathway in development and cancer.
    Dev Cell. 2010 Oct 19;19(4):491-505 PMID: 20951342
  16. Taxol resistance in breast cancer cells is mediated by the hippo pathway component TAZ and its downstream transcriptional targets Cyr61 and CTGF.
    Cancer Res. 2011 Apr 1;71(7):2728-38 PMID: 21349946
  17. Targeting HIF1α eliminates cancer stem cells in hematological malignancies.
    Cell Stem Cell. 2011 Apr 8;8(4):399-411 PMID: 21474104
  18. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells.
    Cell. 2011 Nov 11;147(4):759-72 PMID: 22078877
  19. Hypoxia-inducible factors in physiology and medicine.
    Cell. 2012 Feb 3;148(3):399-408 PMID: 22304911
  20. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia.
    Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2784-9 PMID: 22308314
  21. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs.
    Oncogene. 2012 Apr 5;31(14):1757-70 PMID: 21860410
  22. Hypoxia-inducible factor 1α promotes primary tumor growth and tumor-initiating cell activity in breast cancer.
    Breast Cancer Res. 2012;14(1):R6 PMID: 22225988
  23. Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells.
    Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2707-16 PMID: 23012449
  24. Comprehensive molecular portraits of human breast tumours.
    Nature. 2012 Oct 4;490(7418):61-70 PMID: 23000897
  25. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis.
    J Clin Invest. 2013 Jan;123(1):189-205 PMID: 23318994
  26. Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis.
    Mol Cancer Res. 2013 May;11(5):456-66 PMID: 23378577
  27. Collagen prolyl hydroxylases are essential for breast cancer metastasis.
    Cancer Res. 2013 Jun 1;73(11):3285-96 PMID: 23539444
  28. Emerging roles of TEAD transcription factors and its coactivators in cancers.
    Cancer Biol Ther. 2013 May;14(5):390-8 PMID: 23380592
  29. Role of hypoxia-inducible factors in breast cancer metastasis.
    Future Oncol. 2013 Nov;9(11):1623-36 PMID: 24156323
  30. Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells.
    Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):E384-93 PMID: 24324133
  31. Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer.
    J Mol Med (Berl). 2014 Feb;92(2):151-64 PMID: 24248265
  32. Hypoxia-inducible factor 1 and cardiovascular disease.
    Annu Rev Physiol. 2014;76:39-56 PMID: 23988176
  33. Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WWdomain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer.
    Eur J Cancer. 2013 Jul;49(11):2608-18 PMID: 23566416
  34. Metastatic stem cells: sources, niches, and vital pathways.
    Cell Stem Cell. 2014 Mar 6;14(3):306-21 PMID: 24607405
  35. Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency.
    Cell Stem Cell. 2014 May 1;14(5):592-605 PMID: 24656769
  36. Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment.
    Proc Natl Acad Sci U S A. 2014 May 20;111(20):E2120-9 PMID: 24799675
  37. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma.
    Cancer. 2003 Mar 15;97(6):1573-81 PMID: 12627523
  38. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells.
    Genes Dev. 2003 May 15;17(10):1253-70 PMID: 12756227
  39. Tumor hypoxia and malignant progression.
    Methods Enzymol. 2004;381:335-54 PMID: 15063685
  40. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia.
    Cell. 2004 Jun 25;117(7):941-52 PMID: 15210114
  41. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.
    J Biol Chem. 1996 Dec 20;271(51):32529-37 PMID: 8955077
  42. c-erbB-2 related aggressiveness in breast cancer is hypoxia inducible factor-1alpha dependent.
    Clin Cancer Res. 2004 Dec 1;10(23):7972-7 PMID: 15585632
  43. Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer.
    J Clin Pathol. 2005 Feb;58(2):172-7 PMID: 15677538
  44. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties.
    Cancer Res. 2005 Jul 1;65(13):5506-11 PMID: 15994920
  45. Overexpression of hypoxia-inducible factor HIF-1alpha predicts early relapse in breast cancer: retrospective study in a series of 745 patients.
    Int J Cancer. 2005 Sep 20;116(5):734-9 PMID: 15849727
  46. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival.
    Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5 PMID: 16141321
  47. Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts.
    Breast Cancer Res. 2005;7(6):R953-64 PMID: 16280042
  48. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis.
    J Natl Cancer Inst. 2006 Feb 15;98(4):262-72 PMID: 16478745
  49. Hypoxia inducible factor-1alpha is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response.
    Int J Cancer. 2006 May 15;118(10):2609-16 PMID: 16381002
  50. Lysyl oxidase is essential for hypoxia-induced metastasis.
    Nature. 2006 Apr 27;440(7088):1222-6 PMID: 16642001
  51. Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer.
    Clin Cancer Res. 2006 Aug 1;12(15):4562-8 PMID: 16899602
  52. Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer.
    Cancer Res. 2006 Nov 1;66(21):10292-301 PMID: 17079448
  53. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression.
    Cancer Res. 2007 Jan 15;67(2):563-72 PMID: 17234764
  54. HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome.
    Int J Cancer. 2007 Apr 1;120(7):1451-8 PMID: 17245699
  55. Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.
    J Clin Oncol. 2007 Apr 1;25(10):1239-46 PMID: 17401012
  56. Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer.
    Cancer Res. 2007 May 1;67(9):4157-63 PMID: 17483326
  57. Hypoxia-inducible factor-1alpha correlates with MET and metastasis in node-negative breast cancer.
    Breast Cancer Res Treat. 2007 Jun;103(2):167-75 PMID: 17028975
  58. Analysis of hypoxia-inducible factor 1alpha expression and its effects on invasion and metastasis.
    Methods Enzymol. 2007;435:347-54 PMID: 17998062
Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.2997
Published
2014-12-30
Pages
12509-27
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4350363
Subset
IM
Grants
NCI NIH HHS · R00 CA168746 · United States
NCI NIH HHS · K99 CA181352 · United States
NCI NIH HHS · K99 CA168746 · United States
NCI NIH HHS · K99-CA181352 · United States
NCI NIH HHS · K99-CA168746 · United States
External Links
PubMed source DOI: 10.18632/oncotarget.2997 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2