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Cited by 63Cancer, Hypoxia, and MetabolismVitamin C and Antioxidants ResearchAngiogenesis and VEGF in Cancer

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Activation of the hypoxia pathway in breast cancer tissue and patient survival are inversely associated with tumor ascorbate levels

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Campbell, Elizabeth J., Dachs, Gabi U., Morrin, Helen R., Davey, Valerie C., Robinson, Bridget A., Vissers, Margreet C. M.·2019·BMC Cancer
DOI 10.1186/s12885-019-5503-xPMC PMC6448303
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Abstract

BACKGROUND: The transcription factor hypoxia inducible factor (HIF) -1 drives tumor growth and metastasis and is associated with poor prognosis in breast cancer. Ascorbate can moderate HIF-1 activity in vitro and is associated with HIF pathway activation in a number of cancer types, but whether tissue ascorbate levels influence the HIF pathway in breast cancer is unknown. In this study we investigated the association between tumor ascorbate levels and HIF-1 activation and patient survival in human breast cancer. METHODS: In a retrospective analysis of human breast cancer tissue, we analysed primary tumor and adjacent uninvolved tissue from 52 women with invasive ductal carcinoma. We measured HIF-1α, HIF-1 gene targets CAIX, BNIP-3 and VEGF, and ascorbate content. Patient clinical outcomes were evaluated against these parameters. RESULTS: HIF-1 pathway proteins were upregulated in tumor tissue and increased HIF-1 activation was associated with higher tumor grade and stage, with increased vascular invasion and necrosis, and with decreased disease-free and disease-specific survival. Grade 1 tumors had higher ascorbate levels than did grade 2 or 3 tumors. Higher ascorbate levels were associated with less tumor necrosis, with lower HIF-1 pathway activity and with increased disease-free and disease-specific survival. CONCLUSIONS: Our findings indicate that there is a direct correlation between intracellular ascorbate levels, activation of the HIF-1 pathway and patient survival in breast cancer. This is consistent with the known capacity of ascorbate to stimulate the activity of the regulatory HIF hydroxylases and suggests that optimisation of tumor ascorbate could have clinical benefit via modulation of the hypoxic response.

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  • A retrospective analysis of human patient tumor samples for endometrial cancer, RCC, and CRC revealed that tumors with the highest HIF-1 activity were generally associated with patients who had a notable deficiency in ascorbic acid.

    “Furthermore, a retrospective analysis involving human patient tumor samples paired with controls for endometrial cancer, RCC, and CRC revealed that tumors exhibiting the highest HIF-1 activity were generally associated with patients who had a notable deficiency in ascorbic acid.303”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [303]

    The Background reports retrospective findings in endometrial, colorectal, and papillary renal cell carcinoma tissue: higher tumor ascorbate was associated with lower HIF-1 pathway activity. It does not establish that the patients themselves were deficient in ascorbic acid, and its renal finding is specific to papillary carcinoma rather than RCC generally. The Discussion also reports no such association in clear cell RCC. (LLM, conf=0.86)

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Metadata

Authors
Campbell, E. J., Dachs, G. U., Morrin, H. R., Davey, V. C., Robinson, B. A., & Vissers, M. C. M.
Affiliations
  • University of Otago (NZ)
  • Christchurch Hospital (NZ)
  • Canterbury District Health Board (NZ)
Corresponding author
Vissers, Margreet C. M.
ORCID
Venue
BMC Cancer
Publisher
Springer Science and Business Media LLC
Published
2019-04-03
Volume
19
Issue
1
Pages
307-307
ISSN
1471-2407 (ISSN-L)
DOI
10.1186/s12885-019-5503-x
PMC
PMC6448303
OpenAlex
W2943949980
Cited by
63
References
74
Citations by year
2025: 7 · 2024: 4 · 2023: 6 · 2022: 18 · 2021: 14 · 2020: 14
FWCI
3.64
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Cancer (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Canterbury Medical Research Foundation (R1512)
  • New Zealand Breast Cancer Foundation (R1512)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
breast cancer, HIF-1, vitamin C, HIF-1α, tumor hypoxia, invasive ductal carcinoma, patient survival, CAIX, BNIP3, vascular endothelial growth factor, tumor grade, tumor necrosis, disease-free survival, disease-specific survival
MeSH terms
Carbonic Anhydrase IX, Antigens, Neoplasm, Ascorbic Acid, Breast Neoplasms, Female, Humans, Membrane Proteins, Middle Aged, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins, Retrospective Studies, Cell Hypoxia, Up-Regulation, Gene Expression Regulation, Neoplastic, Survival Analysis, Carcinoma, Ductal, Breast, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, Neoplasm Grading

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