Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α
By R. Campbell, P. Bhat-Nakshatri, N. Patel, D. Constantinidou, Simak Ali, Harikrishna Nakshatri. Journal of Biological Chemistry, 2001
877 citations recorded by the source corpus.
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 ERα 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 ERα, 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 ERα. The consensus AKT phosphorylation site Ser-167 of ERα is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ERα 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 ERα, and inhibition of tamoxifen-induced apoptotic regression.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/2558a91f797b0cbffb7b58e1a898123c20935031
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Citations in the corpus
- The development of androgen-independent prostate cancer (2001, background): “Recent investigation indicates that the AKT pathway might also be important in the development of tamoxifen-resistant breast cance”
- Endocrine-responsive breast cancer and strategies for combating resistance (2002, background): “ER phosphorylation by AKT occurs at serine 167 and results in ligand-independent activation of E”
- Mechanisms of tamoxifen resistance. (2004, methodology): “Campbell and colleagues transfected MCF7 cells with AKT reducing the inhibition of cell growth by tamoxifen, suggesting that high expression of AKT could be associated with tamoxifen resistance but there are no clinical data to address this (Campbell et al. 2001).”
- Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. (2004, background): “Activation of AKT by these same tyrosine kinase receptors may have a similar effect ( 25 ).”