Phosphatidylinositol-3-OH kinase (PI3K)/AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ER alpha) via interaction between ER alpha and PI3K

We have shown previously that the AKT2 pathway is essential for cell surviv al and important in malignant transformation. In this study, we demonstrate elevated kinase levels of AKT2 and phosphatidylinositol-3-OH kinase (PI3K) in 32 of 80 primary breast carcinomas. The majority of the cases with the activation are estrogen receptor alpha (ER alpha) positive, which prompted us to examine whether AKT2 regulates ER alpha activity. We found that const itutively activated AKT2 or AKT2 activated by epidermal growth factor or in sulin-like growth factor-1 promotes the transcriptional activity of ER alph a. This effect occurred in the absence or presence of estrogen. Activated A KT2 phosphorylates ER alpha in vitro and in vivo, but it does not phosphory late a mutant ER alpha in which ser-167 was replaced by Ala. The PI3K inhib itor, wortmannin, abolishes both the phosphorylation and transcriptional ac tivity of ER alpha induced by AKT2. However, AKT2-induced ER alpha activity was not inhibited by tamoxifen but was completely abolished by ICI 164,384 , implicating that AKT2-activated ER alpha contributes to tamoxifen resista nce. Moreover, we found that ER alpha binds to the p85 alpha regulatory sub unit of PI3K in the absence or presence of estradiol in epithelial cells an d subsequently activates PI3K/AKT2, suggesting ER alpha regulation of PI3K/ AKT2 through a nontranscriptional and ligand-independent mechanism. These d ata indicate that regulation between the ER alpha and PI3K/AKT2 pathway (ER alpha -PI3K/AKT2-ER alpha) may play an important role in pathogenesis of h uman breast cancer and could contribute to ligand-independent breast cancer cell growth.