Hypoxia-inducible factor-1α expression requires PI 3-kinase activity and correlates with Akt1 phosphorylation in invasive breast carcinomas

Abstract

Hypoxia-inducible factor-1 alpha (HIF-1α) is the regulatory subunit of the heterodimeric transcription factor HIF-1 and the key factor in cellular response to low oxygen tension. Expression of HIF-1α protein is associated with poor patient survival and therapy resistance in many types of solid tumors. Insight into HIF-1α regulation in solid tumors is important for therapeutic strategies. In this study, we determined the pathophysiological relevance of HIF-1α regulation by the oncogenic phosphatidylinositol 3′-kinase (PI 3-kinase)/Akt signaling pathway. We modeled the physiology of hypoxic tumor regions by culturing carcinoma cells under low oxygen tension in the absence of serum. We observed that hypoxic induction of HIF-1α protein was decreased by serum deprivation. Overexpression of dominant-active Akt1 restored HIF-1α expression, whereas inhibition of PI 3-kinase activity reduced hypoxic HIF-1α protein levels to a similar extent as serum deprivation. Immunohistochemical analysis of 95 human breast cancers revealed that lack of Akt1 phosphorylation correlates with low HIF-1α levels. To our knowledge, this is the first reported comparison between HIF-1α expression and Akt phosphorylation in human carcinomas. We conclude that Akt activity is physiologically relevant for HIF-1α expression in breast cancer. This implies that HIF-1α function might be therapeutically targeted by inhibition of the PI 3-kinase/Akt pathway.