Forkhead Box Transcription Factor FOXO3a Regulates Estrogen Receptor Alpha Expression and Is Repressed by the Her-2/neu/Phosphatidylinositol 3-Kinase/Akt Signaling Pathway

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Abstract
The expression status of the estrogen receptor alpha (ERα) and that of the epidermal growth factor receptor Her-2/neu frequently correlate inversely in breast cancers. While ERα-dependent cancers respond to antiestrogen therapy, Her-2/neu-overexpressing cancers typically display resistance to antiestrogens and poor prognosis. In this report we have explored the mechanism linking the loss of expression of ERα in breast cancer cells with overexpression of Her-2/neu, which signals constitutively via a phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathway. We identify for the first time the Forkhead box protein FOXO3a (formerly termed FKHRL-1), which is inactivated by Akt, as a key regulator of ERα gene transcription. In breast cancer cell lines, expression of ERα was correlated with active FOXO3a levels. Ectopic FOXO3a expression induced ERα protein levels and promoter activity, while a dominant negative FOXO3a decreased ERα levels. By using transient transfection, mobility shift assays, and site-directed mutagenesis, two major functional Forkhead binding sites were identified in the human ERα promoter B. A chromatin immunoprecipitation assay confirmed FOXO3a binding at these two sites. Ectopic FOXO3a induced estrogen response element-driven reporter activity and expression of ERα target genes. The constitutively activated myristylated Akt reduced ERα expression, whereas agents that negatively affect the PI3K/Akt pathway, i.e., wortmannin, celecoxib, and the green tea polyphenol epigallocatechin-3 gallate, induced ERα. Thus, FOXO3a represents an important intracellular mediator of ERα expression, suggesting possible therapeutic intervention strategies for Her-2/neu-overexpressing refractory breast tumors.

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