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Estrogen Receptor Regulation of Carbonic Anhydrase XII through a Distal Enhancer in Breast Cancer

Departments of ¹ Cell and Developmental Biology, ² Molecular and Integrative Physiology, ³ Bioengineering, and ⁴ College of Medicine, University of Illinois at Urbana-Champaign, Urbana, Illinois; ⁵ Edward A. Doisy Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri; ⁶ Department of Microbiology and Molecular Biology, Brigham Young University, Provo, Utah; and ⁷ Genome Institute of Singapore, Singapore

Requests for reprints: Benita S. Katzenellenbogen, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, IL 61801-3704. Phone: 217-333-9769; Fax: 217-244-9906; E-mail: katzenel{at}life.uiuc.edu.

Key Words: estrogen receptor • estradiol • SERM • carbonic anhydrase • gene regulation

The expression of carbonic anhydrase XII (CA12), a gene that encodes a zinc metalloenzyme responsible for acidification of the microenvironment of cancer cells, is highly correlated with estrogen receptor (ER) in human breast tumors. Here, we show that CA12 is robustly regulated by estrogen via ER in breast cancer cells, and that this regulation involves a distal estrogen-responsive enhancer region. Upon the addition of estradiol, ER binds directly to this distal enhancer in vivo, resulting in the recruitment of RNA polymerase II and steroid receptor coactivators SRC-2 and SRC-3, and changes in histone acetylation. Mutagenesis of an imperfect estrogen-responsive element within this enhancer region abolishes estrogen-dependent activity, and chromosome conformation capture and chromatin immunoprecipitation assays show that this distal enhancer communicates with the transcriptional start site of the CA12 gene via intrachromosomal looping upon hormone treatment. This distal enhancer element is observed in the homologous mouse genomic sequence, and the expression of the mouse homologue, Car12, is rapidly and robustly stimulated by estradiol in the mouse uterus in vivo, suggesting that the ER regulation of CA12 is mechanistically and evolutionarily conserved. Our findings highlight the crucial role of ER in the regulation of the CA12 gene, and provide insight into the transcriptional regulatory mechanism that accounts for the strong association of CA12 and ER in human breast cancers. [Cancer Res 2008;68(9):3505–15]

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