The alpha6beta1 integrin has been implicated in breast carcinoma progression, but the mechanisms involved remain elusive. MDA-MB-435 cells engineered to be deficient in alpha6beta1 expression form primary tumors that are highly apoptotic and unable to metastasize, although they exhibit no increased apoptosis in vitro under standard culture conditions. Based on the hypothesis that alpha6beta1 is necessary for the survival of these cells in the tumor microenvironment, we report here that hypoxia protects these cells from apoptosis induced by serum deprivation and that hypoxia-mediated protection requires alpha6beta1 expression. We investigated the influence of alpha6beta1 on vascular endothelial growth factor (VEGF) expression because autocrine VEGF is necessary for the survival of serum-deprived cells in hypoxia. The results obtained indicate that alpha6beta1 is necessary for VEGF expression because the ability of hypoxia to activate HIF-1 and to stimulate VEGF transcription in MDA-MB-435 cells is dependent on alpha6beta1 expression by a mechanism that involves protein kinase C-alpha.