Levels of hypoxia-inducible factor-1α during breast carcinogenesis

Reinhard Bos, Hua Zhong, Colleen F. Hanrahan, Ellen C.M. Mommers, Gregg L. Semenza, Herbert M. Pinedo, Martin D. Abeloff, Jonathan W. Simons, Paul J. Van Diest, Elsken Van Der Wall

Research output: Contribution to journalArticle

Abstract

Background: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In this report, we investigated whether the level of HIF-1α is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers. Methods: Paraffin-embedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1α protein and the biomarkers vascular endothelial growth factor (VEGF), HER-2/neu, p53, Ki-67, and estrogen receptor (ER) were identified immunohistochemically, and microvessel density (a measure of angiogenesis) was determined. Associations among levels of HIF-1α and these biomarkers were tested statistically. All statistical tests are two-sided. Results: The frequency of HIF-1α-positive cells in a specimen increased with the specimen's pathologic stage (P<.001, Χ2 test for trend) as follows: normal breast tissue (0 specimens with ≥1% HIF-1α-positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas in situ (DCIS) (11 in 20), well-differentiated invasive breast cancers (12 in 20), poorly differentiated DCIS (17 in 20), and poorly differentiated invasive carcinomas (20 in 20). Increased levels of HIF-1α were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1α were statistically significantly associated with increased microvessel density. HIF-1α showed a borderline association with HER-2/neu but no association with p53. Conclusions: The level of HIF-1α increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1α are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1α are potentially associated with more aggressive tumors.

Original languageEnglish (US)
Pages (from-to)309-314
Number of pages6
JournalJournal of the National Cancer Institute
Volume93
Issue number4
DOIs
StatePublished - Feb 21 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bos, R., Zhong, H., Hanrahan, C. F., Mommers, E. C. M., Semenza, G. L., Pinedo, H. M., Abeloff, M. D., Simons, J. W., Van Diest, P. J., & Van Der Wall, E. (2001). Levels of hypoxia-inducible factor-1α during breast carcinogenesis. Journal of the National Cancer Institute, 93(4), 309-314. https://doi.org/10.1093/jnci/93.4.309