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Molecular and Cellular Biology, October 2004, p. 8681-8690, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8681-8690.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Department of Biochemistry and Program in Research on Women's Health, Boston University School of Medicine, Boston, Massachusetts

Received 10 February 2004/ Returned for modification 19 April 2004/ Accepted 22 June 2004

The expression status of the estrogen receptor alpha (ER) and that of the epidermal growth factor receptor Her-2/neu frequently correlate inversely in breast cancers. While ER-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 ER 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 ER gene transcription. In breast cancer cell lines, expression of ER was correlated with active FOXO3a levels. Ectopic FOXO3a expression induced ER protein levels and promoter activity, while a dominant negative FOXO3a decreased ER levels. By using transient transfection, mobility shift assays, and site-directed mutagenesis, two major functional Forkhead binding sites were identified in the human ER 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 ER target genes. The constitutively activated myristylated Akt reduced ER expression, whereas agents that negatively affect the PI3K/Akt pathway, i.e., wortmannin, celecoxib, and the green tea polyphenol epigallocatechin-3 gallate, induced ER. Thus, FOXO3a represents an important intracellular mediator of ER expression, suggesting possible therapeutic intervention strategies for Her-2/neu-overexpressing refractory breast tumors.

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