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J. Biol. Chem., Vol. 281, Issue 27, 18825-18836, July 7, 2006

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A Novel Estradiol/Estrogen Receptor -dependent Transcriptional Mechanism Controls Expression of the Human Prolactin Receptor^*

From the Section on Molecular Endocrinology, Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892

Prolactin exerts diverse functions in target tissues through its membrane receptors, and is a potent mitogen in normal and neoplastic breast cells. Estradiol (E₂) induces human prolactin receptor (hPRLR) gene expression through stimulation of its generic promoter (PIII). This study identifies a novel E₂-regulated non-estrogen responsive element-dependent transcriptional mechanism that mediates E₂-induced hPRLR expression. E₂ stimulated transcriptional activity in MCF7A₂ cells transfected with PIII lacking an estrogen responsive element, and increased hPRLR mRNA and protein. The abolition of the E₂ effect by mutation of Sp1 or C/EBP elements that bind Sp1/Sp3 and C/EBP within PIII indicated the cooperation of these transfactors in E₂-induced transcription of the hPRLR. DNA affinity protein assay showed that E₂ induced estrogen receptor (ER) binding to Sp1/Sp3 and C/EBP DNA-protein complexes. The ligand-binding domain of ER was essential for its physical interaction with C/EBP, and E₂ promoted this association, and its DNA binding domain was required for transactivation of PIII. Co-immunoprecipitation studies revealed tethering of C/EBP to Sp1 by E₂-activated ER. Chromatin immunoprecipitation analysis showed that E₂ induced recruitment of C/EBP, ER, SRC1, p300, pCAF, TFIIB, and Pol II, with no change in Sp1/Sp3. E₂ also induced promoter-associated acetylation of H3 and H4. These findings demonstrate that an E₂/ER, Sp1, and C/EBP complex with recruitment of coactivators and TFIIB and Pol II are required for E₂-activated transcriptional expression of the hPRLR through PIII. Estradiol produced in breast stroma and adipose tissue, which are major sources of estrogen in post-menopausal women, could up-regulate hPRLR gene expression and stimulate breast tumor growth.

Received for publication, December 1, 2005 , and in revised form, April 13, 2006.

^* This work was supported by the Intramural Research Program of the NICHD, National Institutes of Health. 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 To whom correspondence should be addressed: ERRB, NICHD, National Institutes of Health, Bldg. 49, Rm. 6A-36, 49 Convent Dr., MSC 4510, Bethesda, MD 20892-4510. Tel.: 301-496-2021; Fax: 301-480-8010; E-mail: dufaum{at}mail.nih.gov.

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