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J. Biol. Chem., Vol. 281, Issue 5, 2585-2597, February 3, 2006

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A Novel Role of Sodium Butyrate in the Regulation of Cancer-associated Aromatase Promoters I.3 and II by Disrupting a Transcriptional Complex in Breast Adipose Fibroblasts^*

From the Division of Reproductive Biology Research, Northwestern University, Chicago, Illinois 60611

The aromatase gene encodes the key enzyme for estrogen formation. Aromatase enzyme inhibitors eliminate total body estrogen production and are highly effective therapeutics for postmenopausal breast cancer. A distal promoter (I.4) regulates low levels of aromatase expression in tumor-free breast adipose tissue. Two proximal promoters (I.3/II) strikingly induce in vivo aromatase expression in breast fibroblasts surrounding malignant cells. Treatment of breast fibroblasts with medium conditioned with malignant breast epithelial cells (MCM) or a surrogate hormonal mixture (dibutyryl (Bt₂)cAMP plus phorbol diacetate (PDA)) induces promoters I.3/II. The mechanism of promoter-selective expression, however, is not clear. Here we reported that sodium butyrate profoundly decreased MCM- or Bt₂cAMP + PDA-induced promoter I.3/II-specific aromatase mRNA. MCM, Bt₂cAMP + PDA, or sodium butyrate regulated aromatase mRNA or activity only via promoters I.3/II but not promoters I.1 or I.4 in breast, ovarian, placental, and hepatic cells. Mechanistically, recruitment of phosphorylated ATF-2 by a CRE (–211/–199, promoter I.3/II) conferred inductions by MCM or Bt₂cAMP + PDA. Chromatin immunoprecipitation-PCR and immunoprecipitation-immunoblotting assays indicated that MCM or Bt₂cAMP + PDA stabilized a complex composed of phosphorylated ATF-2, C/EBP, and cAMP-response element-binding protein (CREB)-binding protein in the common regulatory region of promoters I.3/II. Overall, histone acetylation patterns of promoters I.3/II did not correlate with sodium butyrate-dependent silencing of promoters I.3/II. Sodium butyrate, however, consistently disrupted the activating complex composed of phosphorylated ATF-2, C/EBP, and CREB-binding protein. This was mediated, in part, by decreased ATF-2 phosphorylation. Together, these findings represent a novel mechanism of sodium butyrate action and provide evidence that aromatase activity can be ablated in a signaling pathway- and cell-specific fashion.

Received for publication, August 2, 2005 , and in revised form, November 3, 2005.

^* This work was supported by NCI Grant CA67167 from the National Institutes of Health, the AVON Foundation, the Lynn Sage Foundation, and Friends of Prentice. 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.

¹ Both authors contributed equally to this work.

² Present address: TongJi Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China.

³ To whom correspondence should be addressed: Division of Reproductive Biology Research, Feinberg School of Medicine, Northwestern University, 303 Superior St., Ste. 4-123, Chicago, IL 60611. Tel.: 312-503-1600: Fax: 312-503-0095; E-mail: s-bulun{at}northwestern.edu.

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