Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptoralpha - A new model for anti-estrogen resistance

Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response el ements in the promoter region of target genes or through protein-protein in teractions. Anti-estrogens such as tamoxifen inhibit the growth of ER-posit ive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a sig nificant clinical problem. Here we show that phosphatidylinositol (PI) 3-ki nase and AKT activate ER alpha in the absence of estrogen. Although PI 3-ki nase increased the activity of both estrogen-independent activation functio n 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ER alpha, AKT increased the activity of only AF-1, PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI I-kina se utilizes AKT-dependent and AKT-independent pathways in activating ER alp ha. The consensus AKT phosphorylation site Ser-167 of ER alpha is required for phosphorylation and activation by AKT, In addition, LY294002, a specifi c inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ER a lpha in vivo, Moreover, AKT overexpression led to up-regulation of estrogen -regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demons trate that AKT protects breast cancer cells from tamoxifen-induced apoptosi s. Taken together, these results define a molecular link between activation of the PI3-kinase/AKT survival pathways, hormone-independent activation of ER alpha, and inhibition of tamoxifen-induced apoptotic regression.