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-la 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-la 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, X 2 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-la 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-la showed a borderline association with HER-2/neu but no association with p53. Conclusions: The level of HIF-la 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-la are potentially associated with more aggressive tumors.