Differential prognostic impact of hypoxia induced and diffuse HIF-1α expression in invasive breast cancer
Open accessAbstract
Background: Intratumorous hypoxia triggers a broad cellular response mediated by the transcription factor hypoxia inducible factor 1 (HIF-1). HIF-1α concentrations increase during breast carcinogenesis, and are associated with poor prognosis. An earlier study noted two HIF-1α overexpression patterns: diffuse scattered throughout the tissue and confined to perinecrotic cells. Aims: To investigate the prognostic impact of these different HIF-1α overexpression patterns in relation to its downstream effectors carbonic anhydrase (CA) IX and glucose transporter 1 (GLUT-1). Methods: HIF-1α, CA IX, and GLUT-1 expression was studied by immunohistochemistry, including double staining for CA IX and HIF-1α. Clinical data included disease free survival, lymph node status, and tumour size. Results: HIF-1α overexpression (44% of cases) had a perinecrotic (13.5%) or diffuse staining pattern (30.5%). CA IX expression was detectable in 12.5% of breast cancers, whereas GLUT-1 expression was seen in 29%, with both showing perinecrotic membrane staining. Perinecrotic HIF-1α overexpression was highly associated with CA IX and GLUT-1 overexpression, and double staining for HIF-1α and CA IX showed strong expression in the same cells. Diffusely overexpressed HIF-1α was not associated with CA IX or GLUT-1 expression. Patients with diffuse HIF-1α staining had a significantly better prognosis than patients with perinecrotically overexpressed HIF-1α. Conclusions: Different regulation pathways of HIF-1α overexpression exist in breast cancer: (1) hypoxia induced, perinecrotic HIF-1α overexpression with strong expression of hypoxia associated genes (CA IX and GLUT-1), which is associated with a poor prognosis; and (2) diffuse HIF-1α overexpression lacking major hypoxia associated downstream effects, resulting in a more favourable prognosis.
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Because necrosis is associated with extreme hypoxia, HIF activation is commonly seen in peri-necrotic regions, and necrosis plus peri-necrotic HIF expression is significantly associated with poor prognosis in multiple tumor types.
“Since necrosis is associated with extreme hypoxia, activation of HIF is commonly observed in areas surrounding necrotic regions (peri-necrotic regions), and the presence of necrosis combined with peri-necrotic HIF expression is significantly associated with poor prognosis in multiple tumor types [30, 31].”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [30]
The Results (page unavailable) report HIF-1α staining around necrotic areas and a worse prognosis for patients with perinecrotic expression; the paper also describes this pattern as hypoxia-induced. Its prognostic analysis concerns breast cancer, however, and does not establish the claimed association across multiple tumor types. (LLM, conf=0.88)
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- Authors
- Vleugel, M. M., Greijer, A. E., Shvarts, A., van der Groep, P., van Berkel, M., Aarbodem, Y., van Tinteren, H., Harris, A. L., van Diest, P. J., & van der Wall, E.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University Medical Center Utrecht (NL)
- John Radcliffe Hospital (GB)
- ORCID
- Harris, A L
- Venue
- Journal of Clinical Pathology
- Publisher
- BMJ
- Published
- 2005-01-27
- Volume
- 58
- Issue
- 2
- Pages
- 172-177
- ISSN
- 0021-9746 (ISSN-L)
- 1472-4146
- PMC
- PMC1770566
- OpenAlex
- W2127990020
- Cited by
- 227
- References
- 35
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 10 · 2015: 8 · 2014: 10 · 2013: 20 · 2012: 14
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Slovenská Akadémia Vied
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- HIF-1α, invasive breast cancer, intratumoral hypoxia, carbonic anhydrase IX, GLUT1, prognostic factors, disease-free survival, tumor necrosis
- MeSH terms
- Carbonic Anhydrase IX, Antigens, Neoplasm, Breast Neoplasms, Carbonic Anhydrases, Female, Humans, Immunohistochemistry, Monosaccharide Transport Proteins, Necrosis, Neoplasm Invasiveness, Neoplasm Proteins, Prognosis, Transcription Factors, Biomarkers, Tumor, Survival Analysis, Glucose Transporter Type 1, Hypoxia-Inducible Factor 1, alpha Subunit
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