Expression of hypoxia-inducible factor-1alpha and cell cycle proteins in invasive breast cancer are estrogen receptor related.

Background: The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular response to hypoxia. Previous studies showed that concentrations of its subunit HIF-1alpha, as a surrogate for HIF-1 activity, are increased during breast carcinogenesis and can independently predict prognosis in breast cancer. During carcinogenesis, the cell cycle is progressively deregulated, and proliferation rate is a strong prognostic factor in breast cancer. In this study we undertook a detailed evaluation of the relationships between HIF-1alpha and cell cycle-associated proteins.

Methods: In a representative estrogen receptor (ER) group of 150 breast cancers, the expression of HIF-1alpha, vascular endothelial growth factor, the ER, HER-2/neu, Ki-67, cyclin A, cyclin D1, p21, p53, and Bcl-2 was investigated by immunohistochemistry.

Results: High concentrations (5% or more) of HIF-1alpha were associated with increased proliferation as shown by positive correlations with Ki-67 (P < 0.001) and the late S-G2-phase protein cyclin A (P < 0.001), but not with the G1-phase protein cyclin D1. High HIF-1alpha concentrations were also strongly associated with p53 positivity (P < 0.001) and loss of Bcl-2 expression (P = 0.013). No association was found between p21 and HIF-1alpha (P = 0.105) in the whole group of patients. However, the subgroup of ER-positive cancers was characterized by a strong positive association between HIF-1alpha and p21 (P = 0.023), and HIF-1alpha lacked any relation with proliferation.

Conclusion: HIF-1alpha overexpression is associated with increased proliferation, which might explain the adverse prognostic impact of increased concentrations of HIF-1alpha in invasive breast cancer. In ER-positive tumors, HIF-1alpha is associated with p21 but not against proliferation. This shows the importance of further functional analysis to unravel the role of HIF-1 in late cell cycle progression, and the link between HIF-1, p21, and ER.