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Cloning and Characterization of a Novel Endothelial Promoter of the Human CYP19 (Aromatase P450) Gene that Is Up-Regulated in Breast Cancer Tissue

Departments of Obstetrics and Gynecology and Molecular Genetics (S.S., S.E.B.), University of Illinois at Chicago, Chicago, Illinois 60612; Department of Obstetrics and Gynecology (K.T.), Tohoku University School of Medicine, Sendai 980-8574, Japan; and Department of Obstetrics and Gynecology (M.S.), School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, Japan 920-0934

Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D. Departments of Obstetrics and Gynecology and Molecular Genetics, The University of Illinois at Chicago, 820 South Wood Street, M/C 808, Chicago, Illinois 60612. E-mail: sbulun{at}uic.edu.

Intratumoral expression of aromatase P450 (P450arom) promotes the growth of breast tumors via increased local estrogen concentration. We cloned a novel 101-bp untranslated first exon (I.7) that comprises the 5'-end of 29–54% of P450arom transcripts isolated from breast cancer tissues (n = 7). The levels of P450arom transcripts with exon I.7 were significantly increased in breast tumor tissues and adipose tissue adjacent to tumors. We identified a promoter immediately upstream of exon I.7 and mapped this to about 36 kb upstream of ATG translation start site of the CYP19 (aromatase cytochrome P450) gene. Sequence analysis of I.7 revealed a TATA-less promoter containing an initiator, two consensus GATA sites, and cis-regulatory elements found in megakaryocytes and endothelial type promoters. Luciferase activity directed by the promoter I.7 sequence (-299/+81 bp) was 4-fold greater than a minimum length promoter sequence (-35/+81 bp) in human microvascular endothelial cells (HMEC-1), but only 2-fold greater in MCF-7 breast malignant epithelial cells. There was no promoter activity in primary breast adipose fibroblasts. Site-directed mutations demonstrated that maximal basal promoter activity required two GATA motifs at -146/-141 bp and -196/-191 bp. Gel shift and deoxyribonuclease I footprinting assays demonstrated the binding of GATA-2 transcription factor but not GATA-1 to the -196/-191-bp region. Overexpression of GATA-2 in HMEC-1 cells increases promoter I.7 activity by 5-fold. In conclusion, promoter I.7 is a GATA-2-regulated endothelial promoter of the human CYP19 gene and may increase estrogen biosynthesis in vascular endothelial cells of breast cancer. The activity of this promoter may also be important for intracrine and paracrine effects of estrogen on blood vessels.

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Ligands:   17β-Estradiol

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