Home LiteratureArticle Details
PMID: 25559953 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

Hypoxia-inducible factor 1 and breast cancer metastasis.

Journal of Zhejiang University. Science. B ·Vol. 16 ·No. 1 ·2015-01-00 ·Pages 32-43

Liu ZJ, Semenza GL, Zhang HF

Abstract

Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible factor 1 (HIF-1), a master regulator of the hypoxic response, have been extensively studied during these processes. In this review, we focus on the roles of HIF-1 in regulating breast cancer cell metastasis, specifically its effects on multiple key steps of metastasis, such as epithelial-mesenchymal transition (EMT), invasion, extravasation, and metastatic niche formation. We also discuss the roles of HIF-1-regulated non-coding RNAs in breast cancer metastasis, and therapeutic opportunities for breast cancer through targeting the HIF-1 pathway.

Keywords
Breast cancer Hypoxia-inducible factor 1 (HIF-1) Metastasis
MeSH Terms
Animals Breast Neoplasms/metabolism,pathology,therapy Cell Line, Tumor Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic Humans Hypoxia Hypoxia-Inducible Factor 1/metabolism Mammary Neoplasms, Experimental/metabolism,pathology Mice Neoplasm Invasiveness Neoplasm Metastasis Signal Transduction Treatment Outcome
Chemicals
Hypoxia-Inducible Factor 1
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Liu Zhao-Ji
CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China; Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Semenza Gregg L
Zhang Hua-Feng
References (104)
104 references, click to expand
  1. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.
    Science. 2002 Feb 1;295(5556):858-61 PMID: 11823643
  2. Epithelial-mesenchymal transitions in tumour progression.
    Nat Rev Cancer. 2002 Jun;2(6):442-54 PMID: 12189386
  3. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells.
    J Biol Chem. 2002 Oct 11;277(41):38205-11 PMID: 12149254
  4. Prostaglandin E2 induces hypoxia-inducible factor-1alpha stabilization and nuclear localization in a human prostate cancer cell line.
    J Biol Chem. 2002 Dec 20;277(51):50081-6 PMID: 12401798
  5. Leukocyte angiotensin II levels inpatients with essential hypertension:relation to insulin resistance.
    Am J Hypertens. 2003 Feb;16(2):129-34 PMID: 12559679
  6. 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
  7. Targeting HIF-1 for cancer therapy.
    Nat Rev Cancer. 2003 Oct;3(10):721-32 PMID: 13130303
  8. An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole.
    Eur J Cancer. 2003 Nov;39(16):2318-27 PMID: 14556923
  9. Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling.
    J Biol Chem. 2004 Jan 23;279(4):2550-8 PMID: 14600153
  10. Tumor hypoxia and malignant progression.
    Methods Enzymol. 2004;381:335-54 PMID: 15063685
  11. Hypoxia-inducible factor 1 alpha in high-risk breast cancer: an independent prognostic parameter?
    Breast Cancer Res. 2004;6(3):R191-8 PMID: 15084243
  12. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2'-deoxyuridine.
    J Natl Cancer Inst. 1970 Oct;45(4):773-82 PMID: 5513503
  13. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements.
    Cancer Res. 1991 Jun 15;51(12):3316-22 PMID: 2040005
  14. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4 PMID: 7539918
  15. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma.
    Cancer Res. 1996 Mar 1;56(5):941-3 PMID: 8640781
  16. Tumor oxygenation correlates with molecular growth determinants in breast cancer.
    Breast Cancer Res Treat. 1998 Mar;48(2):97-106 PMID: 9596481
  17. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2.
    Cancer Res. 1999 Aug 15;59(16):3915-8 PMID: 10463582
  18. Breast cancer metastasis: markers and models.
    Nat Rev Cancer. 2005 Aug;5(8):591-602 PMID: 16056258
  19. Nitric oxide is a factor in the stabilization of hypoxia-inducible factor-1alpha in cancer: role of free radical formation.
    Cancer Res. 2006 Jan 15;66(2):770-4 PMID: 16424008
  20. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B.
    Cancer Res. 2006 Mar 1;66(5):2725-31 PMID: 16510593
  21. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.
    Cell Metab. 2006 Mar;3(3):177-85 PMID: 16517405
  22. Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation.
    Oncogene. 2006 Apr 13;25(16):2379-92 PMID: 16369494
  23. Lysyl oxidase is essential for hypoxia-induced metastasis.
    Nature. 2006 Apr 27;440(7088):1222-6 PMID: 16642001
  24. 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
  25. Collagen reorganization at the tumor-stromal interface facilitates local invasion.
    BMC Med. 2006;4(1):38 PMID: 17190588
  26. A microRNA signature of hypoxia.
    Mol Cell Biol. 2007 Mar;27(5):1859-67 PMID: 17194750
  27. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells.
    Cell. 2007 Apr 6;129(1):111-22 PMID: 17418790
  28. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.
    Cancer Cell. 2007 May;11(5):407-20 PMID: 17482131
  29. MMP-2, MMP-9 and activin A blood levels in patients with breast cancer or prostate cancer metastatic to the bone.
    Anticancer Res. 2007 May-Jun;27(3B):1519-25 PMID: 17595770
  30. Endothelins and hypoxia-inducible factor in cancer.
    Endocr Relat Cancer. 2007 Jun;14(2):233-44 PMID: 17639040
  31. Detection and characterization of tumor hypoxia using pO2 histography.
    Antioxid Redox Signal. 2007 Aug;9(8):1221-35 PMID: 17536958
  32. The invasive front in endometrial carcinoma: higher proliferation and associated derailment of cell cycle regulators.
    Hum Pathol. 2007 Aug;38(8):1232-8 PMID: 17490724
  33. HIF-dependent antitumorigenic effect of antioxidants in vivo.
    Cancer Cell. 2007 Sep;12(3):230-8 PMID: 17785204
  34. The H19 non-coding RNA is essential for human tumor growth.
    PLoS One. 2007;2(9):e845 PMID: 17786216
  35. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer.
    Nature. 2007 Oct 11;449(7163):682-8 PMID: 17898713
  36. Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression.
    Breast Cancer Res. 2011;13(1):202 PMID: 21392411
  37. Cysteine-rich 61-connective tissue growth factor-nephroblastoma-overexpressed 5 (CCN5)/Wnt-1-induced signaling protein-2 (WISP-2) regulates microRNA-10b via hypoxia-inducible factor-1α-TWIST signaling networks in human breast cancer cells.
    J Biol Chem. 2011 Dec 16;286(50):43475-85 PMID: 22020939
  38. Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA.
    Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3024-9 PMID: 22315424
  39. 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
  40. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy.
    Trends Pharmacol Sci. 2012 Apr;33(4):207-14 PMID: 22398146
  41. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.
    J Mol Med (Berl). 2012 Jul;90(7):803-15 PMID: 22231744
  42. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche.
    Cancer Res. 2012 Aug 15;72(16):3906-11 PMID: 22751463
  43. New insight into the SDF-1/CXCR4 axis in a breast carcinoma model: hypoxia-induced endothelial SDF-1 and tumor cell CXCR4 are required for tumor cell intravasation.
    Mol Cancer Res. 2012 Aug;10(8):1021-31 PMID: 22767589
  44. Differential distribution of miR-20a and miR-20b may underly metastatic heterogeneity of breast cancers.
    Asian Pac J Cancer Prev. 2012;13(5):1901-6 PMID: 22901144
  45. MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways.
    Oncogene. 2012 Sep 13;31(37):4150-63 PMID: 22158050
  46. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness.
    Biochim Biophys Acta. 2012 Dec;1826(2):272-96 PMID: 22579961
  47. 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
  48. Comprehensive molecular portraits of human breast tumours.
    Nature. 2012 Oct 4;490(7418):61-70 PMID: 23000897
  49. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis.
    J Clin Invest. 2013 Jan;123(1):189-205 PMID: 23318994
  50. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts.
    J Biol Chem. 2013 Apr 12;288(15):10819-29 PMID: 23423382
  51. MicroRNA miR-24 enhances tumor invasion and metastasis by targeting PTPN9 and PTPRF to promote EGF signaling.
    J Cell Sci. 2013 Mar 15;126(Pt 6):1440-53 PMID: 23418360
  52. Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis.
    Mol Cancer Res. 2013 May;11(5):456-66 PMID: 23378577
  53. Collagen prolyl hydroxylases are essential for breast cancer metastasis.
    Cancer Res. 2013 Jun 1;73(11):3285-96 PMID: 23539444
  54. c-MYC-regulated miR-23a/24-2/27a cluster promotes mammary carcinoma cell invasion and hepatic metastasis by targeting Sprouty2.
    J Biol Chem. 2013 Jun 21;288(25):18121-33 PMID: 23649631
  55. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression.
    Carcinogenesis. 2013 Aug;34(8):1699-707 PMID: 23740838
  56. MicroRNAs and other non-coding RNAs as targets for anticancer drug development.
    Nat Rev Drug Discov. 2013 Nov;12(11):847-65 PMID: 24172333
  57. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche.
    Oncogene. 2013 Oct 31;32(44):5210-9 PMID: 23208505
  58. Expression of Cox-2 in human breast cancer cells as a critical determinant of epithelial-to-mesenchymal transition and invasiveness.
    Expert Opin Ther Targets. 2014 Feb;18(2):121-35 PMID: 24325753
  59. Long non-coding RNA UCA1 promotes breast tumor growth by suppression of p27 (Kip1).
    Cell Death Dis. 2014;5:e1008 PMID: 24457952
  60. Integrated analysis of microRNA and mRNA expression and association with HIF binding reveals the complexity of microRNA expression regulation under hypoxia.
    Mol Cancer. 2014;13:28 PMID: 24517586
  61. Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent.
    Oncogene. 2014 May 1;33(18):2307-16 PMID: 23686305
  62. Oncofetal H19 RNA promotes tumor metastasis.
    Biochim Biophys Acta. 2014 Jul;1843(7):1414-26 PMID: 24703882
  63. LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis.
    Cell Death Dis. 2014;5:e1287 PMID: 24922071
  64. Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression during epithelial-to-mesenchymal transition of breast cancer cells.
    Breast Cancer Res. 2013;15(6):R113 PMID: 24283570
  65. Urothelial carcinoma associated 1 is a hypoxia-inducible factor-1α-targeted long noncoding RNA that enhances hypoxic bladder cancer cell proliferation, migration, and invasion.
    Tumour Biol. 2014 Jul;35(7):6901-12 PMID: 24737584
  66. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases.
    Cancer Res. 1999 Nov 15;59(22):5830-5 PMID: 10582706
  67. Loss of PTEN facilitates HIF-1-mediated gene expression.
    Genes Dev. 2000 Feb 15;14(4):391-6 PMID: 10691731
  68. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics.
    Cancer Res. 2000 Mar 15;60(6):1541-5 PMID: 10749120
  69. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages.
    Am J Pathol. 2000 Aug;157(2):411-21 PMID: 10934146
  70. Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function.
    Oncogene. 2000 Nov 16;19(48):5435-43 PMID: 11114720
  71. Expression of matrix metalloproteinases 1, 2, 9 and their tissue inhibitors in stage II non-small cell lung cancer: implications for MMP inhibition therapy.
    Oncol Rep. 2001 Mar-Apr;8(2):421-4 PMID: 11182067
  72. Apoptosis, angiogenesis and proliferation: trifunctional measure of tumour response to radiotherapy for oral cancer.
    Oral Oncol. 2001 Feb;37(2):164-71 PMID: 11167144
  73. Metalloproteinases: role in breast carcinogenesis, invasion and metastasis.
    Breast Cancer Res. 2000;2(4):252-7 PMID: 11250717
  74. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression.
    Mol Cell Biol. 2001 Jun;21(12):3995-4004 PMID: 11359907
  75. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity.
    Genes Dev. 2001 Oct 15;15(20):2675-86 PMID: 11641274
  76. Hypoxia and breast cancer: prognostic and therapeutic implications.
    Cell Mol Life Sci. 2007 Dec;64(24):3233-47 PMID: 17957335
  77. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer.
    Clin Cancer Res. 2008 Mar 1;14(5):1340-8 PMID: 18316553
  78. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4.
    Cell. 2008 Apr 4;133(1):66-77 PMID: 18394990
  79. [6]-Gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells.
    J Nutr Biochem. 2008 May;19(5):313-9 PMID: 17683926
  80. Microenvironmental regulation of cancer development.
    Curr Opin Genet Dev. 2008 Feb;18(1):27-34 PMID: 18282701
  81. Transcriptional regulation of cell polarity in EMT and cancer.
    Oncogene. 2008 Nov 24;27(55):6958-69 PMID: 19029937
  82. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth.
    Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19579-86 PMID: 19020076
  83. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche.
    Cancer Cell. 2009 Jan 6;15(1):35-44 PMID: 19111879
  84. Cancer stem cells, hypoxia and metastasis.
    Semin Radiat Oncol. 2009 Apr;19(2):106-11 PMID: 19249648
  85. The basics of epithelial-mesenchymal transition.
    J Clin Invest. 2009 Jun;119(6):1420-8 PMID: 19487818
  86. Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling.
    J Biol Chem. 2009 Aug 21;284(34):22825-33 PMID: 19546228
  87. Molecular imaging of hypoxia with radiolabelled agents.
    Eur J Nucl Med Mol Imaging. 2009 Oct;36(10):1674-86 PMID: 19565239
  88. The oncofetal H19 RNA connection: hypoxia, p53 and cancer.
    Biochim Biophys Acta. 2010 Apr;1803(4):443-51 PMID: 20117150
  89. Therapeutic silencing of miR-10b inhibits metastasis in a mouse mammary tumor model.
    Nat Biotechnol. 2010 Apr;28(4):341-7 PMID: 20351690
  90. miR-20b modulates VEGF expression by targeting HIF-1 alpha and STAT3 in MCF-7 breast cancer cells.
    J Cell Physiol. 2010 Jul;224(1):242-9 PMID: 20232316
  91. Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs.
    Oncogene. 2010 May 6;29(18):2638-48 PMID: 20154725
  92. Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer.
    J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):253-60 PMID: 20354771
  93. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer.
    Oncogene. 2010 Aug 26;29(34):4741-51 PMID: 20531305
  94. Aligned collagen is a prognostic signature for survival in human breast carcinoma.
    Am J Pathol. 2011 Mar;178(3):1221-32 PMID: 21356373
  95. Global cancer statistics.
    CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90 PMID: 21296855
  96. A perspective on cancer cell metastasis.
    Science. 2011 Mar 25;331(6024):1559-64 PMID: 21436443
  97. miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1.
    Oncogene. 2011 May 26;30(21):2463-74 PMID: 21258409
  98. Global microRNA expression profiling identifies MiR-210 associated with tumor proliferation, invasion and poor clinical outcome in breast cancer.
    PLoS One. 2011;6(6):e20980 PMID: 21738599
  99. Oxygen sensing, homeostasis, and disease.
    N Engl J Med. 2011 Aug 11;365(6):537-47 PMID: 21830968
  100. Epidemiological models for breast cancer risk estimation.
    Ginekol Pol. 2011 Jun;82(6):451-4 PMID: 21853936
  101. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation.
    Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16369-74 PMID: 21911388
  102. Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells.
    Oncogene. 2011 Sep 29;30(39):4075-86 PMID: 21499308
  103. ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters.
    Blood. 2011 Oct 6;118(14):3990-4002 PMID: 21841165
  104. Tumor metastasis: molecular insights and evolving paradigms.
    Cell. 2011 Oct 14;147(2):275-92 PMID: 22000009
Article Info
Journal
Journal of Zhejiang University. Science. B
Abbr.
J Zhejiang Univ Sci B
ISSN
1862-1783
DOI
10.1631/jzus.B1400221
Published
2015-01-00
Pages
32-43
Language
English
Region
China
NLM ID
101236535
PMCID
PMC4288942
Subset
IM
External Links
PubMed source DOI: 10.1631/jzus.B1400221 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