TY - JOUR
T1 - Levels of hypoxia-inducible factor-1α during breast carcinogenesis
AU - Bos, Reinhard
AU - Zhong, Hua
AU - Hanrahan, Colleen F.
AU - Mommers, Ellen C.M.
AU - Semenza, Gregg L.
AU - Pinedo, Herbert M.
AU - Abeloff, Martin D.
AU - Simons, Jonathan W.
AU - Van Diest, Paul J.
AU - Van Der Wall, Elsken
PY - 2001/2/21
Y1 - 2001/2/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0035925072&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035925072&partnerID=8YFLogxK
U2 - 10.1093/jnci/93.4.309
DO - 10.1093/jnci/93.4.309
M3 - Article
C2 - 11181778
AN - SCOPUS:0035925072
SN - 0027-8874
VL - 93
SP - 309
EP - 314
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 4
ER -