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

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-1 alpha is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers. Methods: Paraffin-emhedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1 alpha 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-1 alpha and these biomarkers were tested statistically. All statistical tests are two-sided. Results: The frequency of HIF-1 alpha -positive cells in a specimen increased with the specimen's pathologic stage (P<.001, <chi>(2) test for trend) as follows: normal breast tissue (0 specimens with greater than or equal to1% HIF-1 alpha -positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas itt 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-1 alpha were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1 alpha were statistically significantly associated with increased microvessel density. HIF-1 alpha showed a borderline association with HER-2/neu but no association with p53, Conclusions: The level of HIF-1 alpha 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-1 alpha are associated with increased proliferation and increased expression of ER and VEGF, Thus, increased levels of HIF-1 alpha are potentially associated with more aggressive tumors.