Hypoxia-inducible factor-2 alpha (HIF-2 alpha) induces angiogenesis in breast carcinomas

Hypoxia-inducible factors-1alpha (HIF-lalpha) and HIF-2alpha are important proteins initiating tumor cell responses to hypoxia. Specifically, the transcription of genes related to erythropoiesis, glycolysis, and angiogenesis depends on the rate of HIFalpha binding to DNA at the hypoxia response elements of target genes. In this study, the authors evaluated the immunohistochemical expression of HIF-2alpha in 62 infiltrating ductal carcinomas of the breast, not otherwise specified, in relation to estrogen and progesterone receptors, the MIB1 proliferation index, the vascular density, and the proteins c-erbB-2, bcl-2, and p53. Extensive and strong cytoplasmic and/or nuclear expression of HIF-2alpha was noted in 23 of the 64 (35.9%) cases, and this was associated with increased vascular density (P=0.0002), increased c-erbB-2 membrane expression (P=0.02), and secondary deposits to multiple axillary lymph nodes (>3). In multivariate analysis, HIF-2alpha and T stage were the only variables related to extensive nodal metastasis. The authors conclude that HIF-2alpha overexpression, a common event in infiltrating ductal carcinomas of the breast, is related to high metastatic potential via increased angiogenic and c-erbB-2 activity.