Background: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor th
at 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 endothel
ial 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 a
nd these biomarkers were tested statistically. All statistical tests are tw
o-sided. Results: The frequency of HIF-1 alpha -positive cells in a specime
n 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 hype
rplastic 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 c
arcinomas (20 in 20), Increased levels of HIF-1 alpha were statistically si
gnificantly 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 associat
ion with p53, Conclusions: The level of HIF-1 alpha increases as the pathol
ogic 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 expr
ession of ER and VEGF, Thus, increased levels of HIF-1 alpha are potentiall
y associated with more aggressive tumors.