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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

Shangqin Guo and Gail E. Sonenshein*

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

* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Phone: (617) 638-4120. Fax: (617) 638-4252. E-mail: gsonensh{at}bu.edu.

Molecular and Cellular Biology, October 2004, p. 8681-8690, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8681-8690.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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