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

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha protein is associated with poor patient survival and therapy resistance in many types of solid tumors. Insight into HIF-1 alpha regulation in solid tumors is important for therapeutic strategies. In this study, we determined the pathophysiological relevance of HIF-1 alpha 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-1 alpha protein was decreased by serum deprivation. Overexpression of dominant-active Akt1 restored HIF-1 alpha expression, whereas inhibition of PI 3-kinase activity reduced hypoxic HIF-1 alpha 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-1 alpha levels. To our knowledge, this is the first reported comparison between HIF-1 alpha expression and Akt phosphorylation in human carcinomas. We conclude that Akt activity is physiologically relevant for HIF-1 alpha expression in breast cancer. This implies that HIF-1 alpha function might be therapeutically targeted by inhibition of the PI 3-kinase/Akt pathway.