Cited by 278Cancer, Hypoxia, and MetabolismMechanisms of cancer metastasisAngiogenesis and VEGF in Cancer

Role of hypoxia-inducible factors in breast cancer metastasis

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Gilkes, Daniele M, Semenza, Gregg L·2013·Future Oncology

Abstract

Human breast tumors contain regions of hypoxia in which cells that are located far from a functional blood vessel have significantly reduced oxygen concentrations when compared with normal mammary tissue. Breast cancer cells adapt to hypoxic conditions by increasing levels of hypoxia-inducible factors (HIFs), which induce the expression of multiple genes involved in angiogenesis, glucose utilization, resistance to oxidative stress, cell proliferation, resistance to apoptosis, invasion and metastasis. Breast cancer patients with increased HIF expression levels in primary tumor biopsies are at increased risk of metastasis. This is an important finding since 90% of breast cancer deaths are the result of metastasis, primarily to the bone, lungs, liver, brain and regional lymph nodes. Although the prognostic significance of reduced oxygen levels in primary breast tumors of cancer patients is well recognized, the mechanisms underlying hypoxia-induced, HIF-dependent breast cancer metastasis are just beginning to be uncovered. Recent studies have implicated HIF target genes in every step of the metastatic process. Drugs, such as digoxin, show the potential therapeutic effects of blocking HIF activity by decreasing primary tumor growth, vascularization, invasion and metastasis in animal models of breast cancer.

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  1. Vaupel P Hockel M Mayer A Detection and characterization of tumor hypoxia using pO2 histography Antioxid Redox Signal 9 8 1221 1235 2007 Data from 125 studies describing the pretreatment oxygenation status of tumors compared with normal tissue 17536958
  2. [54]Graham CH Forsdike J Fitzgerald CJ Macdonald-Goodfellow S Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression Int J Cancer 80 4 617 623 1999 9935166

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Authors
Gilkes, D. M., & Semenza, G. L.
Affiliations
Johns Hopkins University (US)
Venue
Future Oncology
Published
2013-10-24
Volume
9
Issue
11
Pages
1623-1636
ISSN
  • 1479-6694 (ISSN-L)
  • 1744-8301
OpenAlex
W2126797928
Cited by
274
References
126
Citations by year
2026: 2 · 2025: 17 · 2024: 20 · 2023: 22 · 2022: 24 · 2021: 40 · 2020: 26 · 2019: 29 · 2018: 25 · 2017: 22 · 2016: 15 · 2015: 17 · 2014: 12 · 2013: 1
FWCI
1.24
Type
journal article
Language
en
Open access
Locations
  • Future Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (U54-CA143868)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
hypoxia-inducible factor, breast cancer metastasis, tumor hypoxia, angiogenesis, glucose metabolism, oxidative stress resistance, apoptosis resistance, cell invasion, HIF target genes, prognostic factors, digoxin, HIF inhibitors, tumor vascularization
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Animals, Antineoplastic Agents, Breast Neoplasms, Cell Movement, Cell Survival, Female, Humans, Lymphatic Metastasis, Neoplasm Invasiveness, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, Epithelial-Mesenchymal Transition, Tumor Microenvironment

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