A new model for anti-estrogen resistance is presented, showing that phosphatidylinositol 3-kinase (PI 3-kinase) and AKT activate estrogen receptor alpha (ERα) in the absence of estrogen. PI 3-kinase increases the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERα, while AKT specifically increases AF-1 activity. PTEN and a catalytically inactive AKT reduce PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways to activate ERα. The consensus AKT phosphorylation site Ser-167 of ERα is required for phosphorylation and activation by AKT. LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduces phosphorylation of ERα in vivo. AKT overexpression leads to up-regulation of estrogen-regulated genes such as pS2, Bcl-2, and macrophage inhibitory cytokine 1. The study demonstrates that AKT protects breast cancer cells from tamoxifen-induced apoptosis. These results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERα, and inhibition of tamoxifen-induced apoptotic regression. Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. The study shows that PI 3-kinase and AKT activate ERα in the absence of estrogen. Growth factors such as epidermal growth factor (EGF), insulin-like growth factor (IGF-1), and heregulin confer estrogen-independent growth properties to ERα-positive breast cancer cells. It is suggested that EGF- and IGF-1-induced mitogen-activated protein kinase (MAPK) phosphorylates Ser-118 of ERα, increases the activity of AF-1, and confers hormone-independent growth. However, a recent study indicates that prolonged activation of MAPK is growth inhibitory in breast cancer cells, while parallel activation of the PI 3-kinase/AKT pathway by EGF and IGF-1 is sufficient to overcome such inhibition. Therefore, these growth factors may utilize the PI 3-kinase/AKT pathway to activate ERα and confer hormone-independent growth. Growth factor-dependent survival of a wide variety of cultured cell types ranges from fibroblasts to neurons is dependentA new model for anti-estrogen resistance is presented, showing that phosphatidylinositol 3-kinase (PI 3-kinase) and AKT activate estrogen receptor alpha (ERα) in the absence of estrogen. PI 3-kinase increases the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERα, while AKT specifically increases AF-1 activity. PTEN and a catalytically inactive AKT reduce PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKT-dependent and AKT-independent pathways to activate ERα. The consensus AKT phosphorylation site Ser-167 of ERα is required for phosphorylation and activation by AKT. LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduces phosphorylation of ERα in vivo. AKT overexpression leads to up-regulation of estrogen-regulated genes such as pS2, Bcl-2, and macrophage inhibitory cytokine 1. The study demonstrates that AKT protects breast cancer cells from tamoxifen-induced apoptosis. These results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ERα, and inhibition of tamoxifen-induced apoptotic regression. Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. The study shows that PI 3-kinase and AKT activate ERα in the absence of estrogen. Growth factors such as epidermal growth factor (EGF), insulin-like growth factor (IGF-1), and heregulin confer estrogen-independent growth properties to ERα-positive breast cancer cells. It is suggested that EGF- and IGF-1-induced mitogen-activated protein kinase (MAPK) phosphorylates Ser-118 of ERα, increases the activity of AF-1, and confers hormone-independent growth. However, a recent study indicates that prolonged activation of MAPK is growth inhibitory in breast cancer cells, while parallel activation of the PI 3-kinase/AKT pathway by EGF and IGF-1 is sufficient to overcome such inhibition. Therefore, these growth factors may utilize the PI 3-kinase/AKT pathway to activate ERα and confer hormone-independent growth. Growth factor-dependent survival of a wide variety of cultured cell types ranges from fibroblasts to neurons is dependent