Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture

• Published in: Journal of steroid biochemistry and molecular biology Vol. 61; no. 3; pp. 203 - 210
• Main Authors: Zhao, Ying, Agarwal, Veena R., Mendelson, Carole R., Simpson, Evan R.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Oxford Elsevier Ltd 01-04-1997; Elsevier Science
• Subjects: Adipose Tissue - enzymology; Analytical, structural and metabolic biochemistry; Aromatase - biosynthesis; Aromatase - genetics; Biological and medical sciences; Cells, Cultured; Enzymes and enzyme inhibitors; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Humans; Oxidoreductases; Stromal Cells - enzymology; Transcription, Genetic; Transcriptional Activation; Human; Cell culture; Adipose tissue; Enzyme; Transcription promoter; Arachidonic acid derivatives; Cytochrome P450; Prostaglandin E2; Estrogen synthase; Gene expression; Regulation(control); Primary culture; Female; Stromal cell
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/S0960-0760(97)80013-1

Estrogen biosynthesis in adipose tissue increases with age and obesity, and has been implicated in the development of endometrial cancer and breast cancer. In normal human adipose tissue, expression of the
CYP19 gene which encodes aromatase P450, the enzyme responsible for estrogen biosynthesis, is regulated by a distal promoter, namely promoter I.4. Stimulation of expression in adipose stromal cells by members of the type 1 cytokine family, i.e. interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), is mediated via a Jak-STAT3 signaling pathway and a GAS element upstream of promoter I.4. In contrast, aromatase expression in breast adipose tissue proximal to tumor is increased three- to four-fold to the utilization of another promoter, namely promoter II, proximal to the translation initiation site. In the present report, we show that prostaglandin (PG) E
2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE
2 acts via EP
1 and EP
2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in the maximal expression of promoter II-specific
CYP19 transcripts. Because PGE
2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.