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J. Biol. Chem., Vol. 283, Issue 6, 3433-3444, February 8, 2008

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EP₂ and EP₄ Receptors Regulate Aromatase Expression in Human Adipocytes and Breast Cancer Cells

EVIDENCE OF A BRCA1 AND p300 EXCHANGE^*

Kotha Subbaramaiah¹, Clifford Hudis, Sung-Hee Chang^¶, Timothy Hla^¶, and Andrew J. Dannenberg

From the Department of Medicine, Weill Cornell Medical College, New York, New York 10065, the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065 and the ^¶Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030-3501

Cytochrome P450 aromatase (aromatase), a product of the CYP19 gene, catalyzes the synthesis of estrogens from androgens. Because aromatase-dependent estrogen biosynthesis has been linked to hormone-dependent breast carcinogenesis, it is important to elucidate the mechanisms that regulate CYP19 gene expression. The main objective of this study was to identify the receptors (EP) for prostaglandin E₂ (PGE₂) that mediate the induction of CYP19 transcription in human adipocytes and breast cancer cells. Treatment with PGE₂ induced aromatase, an effect that was mimicked by either EP₂ or EP₄ agonists. Antagonists of EP₂ or EP₄ or small interference RNA-mediated down-regulation of these receptors suppressed PGE₂-mediated induction of aromatase. PGE₂ via EP₂ and EP₄ stimulated the cAMPprotein kinase A pathway resulting in enhanced interaction between P-CREB, p300, and the aromatase promoter I.3/II. Overexpressing a mutant form of p300 that lacks histone acetyltransferase activity suppressed PGE₂-mediated induction of aromatase promoter activity. PGE₂ via EP₂ and EP₄ also caused a reduction in both the amounts of BRCA1 and the interaction between BRCA1 and the aromatase promoter I.3/II. Activation of the aromatase promoter by PGE₂ was suppressed by overexpressing wild-type BRCA1. Silencing of EP₂ or EP₄ also blocked PGE₂-mediated induction of the progesterone receptor, a prototypic estrogen-response gene. In a mouse model, overexpressing COX-2 in the mammary gland, a known inducer of PGE₂ synthesis, led to increased aromatase mRNA and activity and reduced amounts of BRCA1; these effects were reversed by knocking out EP₂. Taken together, these results suggest that PGE₂ via EP₂ and EP₄ activates the cAMPPKACREB pathway leading to enhanced CYP19 transcription and increased aromatase activity. Reciprocal changes in the interaction between BRCA1, p300, and the aromatase promoter I.3/II contributed to the inductive effects of PGE₂.

Received for publication, July 2, 2007 , and in revised form, December 13, 2007.

^* This work was supported by National Institutes of Health Grant PO1CA77839, the Breast Cancer Research Foundation, the Botwinick-Wolfensohn Foundation (in memory of Mr. and Mrs. Benjamin Botwinick), and the Center for Cancer Prevention Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: New York Presbyterian Hospital-Cornell, 525 East 68th St., Rm. F-203A, New York, NY 10065. Tel.: 212-746-4402; Fax: 212-746-4885; E-mail: ksubba{at}med.cornell.edu.

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