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J. Biol. Chem., Vol. 276, Issue 13, 9817-9824, March 30, 2001
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From the Departments of 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. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ER Surgery and
Biochemistry and Molecular Biology and § Walther
Oncology Center, Indiana University School of Medicine, Indianapolis,
Indiana 46202 and the ¶ Department of Cancer Medicine, Imperial
College School of Medicine, Hammersmith Hospital,
London W12 0NN, United Kingdom
in the absence of estrogen. Although PI 3-kinase increased the activity of both
estrogen-independent activation function 1 (AF-1) and
estrogen-dependent activation function 2 (AF-2) of ER, 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
3-kinase utilizes AKT-dependent and AKT-independent
pathways in activating ER. The consensus AKT phosphorylation site
Ser-167 of ER is required for phosphorylation and activation by AKT.
In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT
pathway, reduced phosphorylation of ER in vivo.
Moreover, AKT overexpression led to up-regulation of estrogen-regulated
pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate
that AKT protects breast cancer cells from tamoxifen-induced apoptosis.
Taken together, these results define a molecular link between
activation of the PI 3-kinase/AKT survival pathways,
hormone-independent activation of ER, and inhibition of
tamoxifen-induced apoptotic regression.
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