Translational studies on aromatase, cyclooxygenases, and enzyme inhibitors in breast cancer
| Autor: | Robert W. Brueggemeier, Charles L. Shapiro, Yasuro Sugimoto, Edgar S. Diaz-Cruz, Young C. Lin, Pui-Kai Li |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Small interfering RNA
Transcription Genetic medicine.drug_class Endocrinology Diabetes and Metabolism Clinical Biochemistry Breast Neoplasms Pharmacology Biochemistry Aromatase Endocrinology Breast cancer Gene expression medicine Humans Cyclooxygenase Inhibitors RNA Messenger RNA Small Interfering Promoter Regions Genetic Autocrine signalling Molecular Biology Cells Cultured Cyclooxygenase 2 Inhibitors biology Membrane Proteins Cell Biology medicine.disease Autocrine Communication Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Estrogen Enzyme inhibitor Protein Biosynthesis Cyclooxygenase 1 biology.protein Molecular Medicine Female RNA Interference Cyclooxygenase |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 95:129-136 |
| ISSN: | 0960-0760 |
| DOI: | 10.1016/j.jsbmb.2005.04.013 |
| Popis: | Aromatase expression and enzyme activity in breast cancer patients is greater in or near the tumor tissue compared with the normal breast tissue. Regulation of aromatase expression in human tissues is quite complex, involving alternative promoter sites that provide tissue-specific control. Previous studies in our laboratories suggested a strong association between aromatase (CYP19) gene expression and the expression of cyclooxygenase (COX) genes. Our hypothesis is that higher levels of COX expression result in higher levels of prostaglandin E2 (PGE2), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels. This biochemical mechanism may explain the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) on reducing the risks of breast cancer. The effects of NSAIDs (ibuprofen, piroxicam, and indomethacin), a COX-1 selective inhibitor (SC-560), and COX-2 selective inhibitors (celecoxib, niflumic acid, nimesulide, NS-398, and SC-58125) on aromatase activity and CYP19 expression were investigated in breast cancer cell culture systems. Dose-dependent decreases in aromatase activity were observed following treatment with an NSAID or COX inhibitor, with the most effective agents being COX selective inhibitors. Real time PCR analysis of aromatase gene expression showed a significant decrease in mRNA levels in treated cells when compared to vehicle control. These results suggest that the effect of COX inhibitors on aromatase occurs at the transcriptional level. To further probe these interactions, short interfering RNAs (siRNA) were designed against either human CYP19 mRNA or human COX-2 mRNA. Treatment of breast cancer cells with aromatase siRNAs suppressed CYP19 mRNA and aromatase enzyme activity. Finally, treatment with COX-2 siRNAs downregulated the expression of COX-2 mRNA; furthermore, the siCOX-2-mediated suppression of COX-2 also resulted in suppression of aromatase mRNA. In summary, pharmacological regulation of aromatase and cyclooxygenases can act locally in an autocrine fashion to decrease the biosynthesis of estrogen and may provide additional therapy options for patients with hormone-dependent breast cancer. |
| Databáze: | OpenAIRE |
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