RESUMO
Aromatase, the enzyme system catalyzing estrogen biosynthesis, is found in stromal tissue in the breast. The increased expression of the aromatase CYP19 gene in breast cancer tissues was recently associated with a promoter region regulated through cAMP-mediated pathways. PGE2, derived from cyclooxygenase, increases intracellular cAMP levels and stimulates estrogen biosynthesis. This association suggest that local production of PGE2 via cyclooxgenase isozymes may influence estrogen biosynthesis. The present study represents the first to examine the levels of mRNA expression of CYP19, COX-1, and COX-2 genes in human breast cancer specimens and normal breast tissue samples using semi-quantitative RT-PCR methods. Positive correlations were observed between CYP19 and COX-2 and the greater extent of breast cancer cellularity. Linear regression analysis using a bivariate model shows a strong linear association between CYP19 expression and the sum of COX-1 and COX-2 expression. This significant relationship between the aromatase and cyclooxygenase enzyme systems suggests that autocrine and paracrine mechanisms may be involved in hormone-dependent breast cancer development via growth stimulation from local estrogen biosynthesis.
Assuntos
Aromatase/biossíntese , Neoplasias da Mama/metabolismo , Expressão Gênica , Prostaglandina-Endoperóxido Sintases/biossíntese , Neoplasias da Mama/patologia , Contagem de Células , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Feminino , Humanos , Inflamação/patologia , Isoenzimas/biossíntese , Modelos Lineares , Proteínas de Membrana , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
A single dose of 75 mg/kg 7,12 dimethylbenz[a]anthracene was administered to 50-day-old virgin female Sprague-Dawley rats and 100 days later, animals were randomized and provided with Teklad rodent chow mixed with a dose of 25 mg/rat/day ibuprofen for 35 days. Ibuprofen treatment reduced tumor volume (P < 0.05) and significantly inhibited gene expression of both cyclooxygenase- and cyclooxygenase-2 (P < 0.02). These results indicate that ibuprofen induced significant regression of established mammary carcinomas which was associated with inhibition of expression of isoforms of the gene responsible for prostaglandin production.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Ibuprofeno/farmacologia , Neoplasias Mamárias Experimentais/enzimologia , Prostaglandina-Endoperóxido Sintases/genética , 9,10-Dimetil-1,2-benzantraceno , Animais , Feminino , Neoplasias Mamárias Experimentais/induzido quimicamente , Ratos , Ratos Sprague-DawleyRESUMO
Expression of the inducible isoform of the cyclooxygenase gene (PGHS-2, COX-2) which codes for the enzyme that catalyzes formation of prostaglandins, was detected in 13/13 human breast tumors of high grade but not in samples of normal breast tissue. There was a statistically significant linear association between COX-2 gene expression and high (>50%) tumor cell density (p<0.01), with COX-2 protein localized to tumor cells. These results indicate that COX-2 gene expression may be useful as a molecular biomarker for human breast tumors and may also predict sensitivity to treatment with nonsteroidal anti-inflammatory drugs.
RESUMO
We examined effects of ibuprofen on the growth and development of DMBA-induced mammary cancers in mature female Sprague-Dawley rats. Ibuprofen was added to the standard diet at approximately 1,000 mg/kg rodent chow, resulting in an average daily dose of 25 mg per day per 0.25 kg rat. After five weeks of ibuprofen treatment, there was a 37% reduction in tumor volume compared to a 260% increase in the volume of tumors in untreated rats (p<0.001). These results suggest that ibuprofen may have potential in the chemoprevention and treatment of breast cancer.
