Akt1 governs breast cancer progression in vivo

The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Here, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse demonstrates a requirement for Akt1 in ErbB2-induced mammary tumorigenesis. Aktl deficiency delayed tumor growth and reduced lung metastases, correlating with a reduction in phosphorylation of the Aktl target, tuberous sclerosis 2 (TSC2) at Ser-939. Akt1-deficient mammary epithelial tumor cells (MEC) were reduced in size and proliferative capacity, with reduced cyclin D1 and p27(KIP1) abundance. Aktl deficiency abrogated the oncogene-induced changes in polarization of MEC in three-dimensional culture and reverted oncogene-induced relocalization of the phosphorylated ezrin-radixin-moesin proteins. Aktl increased MEC migration across an endothelial cell barrier, enhancing the persistence of migratory directionality. An unbiased proteomic analysis demonstrated Aktl mediated MEC migration through paracrine signaling via induction of expression and secretion of CXCL16 and MlP1 gamma. Aktl governs MEC polarity, migratory directionality and breast cancer onset induced by ErbB2 in vivo.