Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells.
BACKGROUND
Melatonin reduces the development of breast cancer interfering with oestrogen-signalling pathways, and also inhibits aromatase activity and expression. Our objective was to study the promoters through which melatonin modifies aromatase expression, evaluate the ability of melatonin to regulate cyclooxygenases and assess whether the effects of melatonin are related to its effects on intracellular cAMP, in MCF-7 cells.


METHODS
Total aromatase mRNA, aromatase mRNA promoter regions and cyclooxygenases mRNA expression were determined by real-time RT-PCR. PGE(2) and cAMP were measured by kits.


RESULTS
Melatonin downregulated the gene expression of the two major specific aromatase promoter regions, pII and pI.3, and also that of the aromatase promoter region pI.4. Melatonin 1 nM was able to counteract the stimulatory effect of tetradecanoyl phorbol acetate on PGE(2) production and inhibit COX-2 and COX-1 mRNA expression. Melatonin 1 nM elicited a parallel time-dependent decrease in both cyclic AMP formation and aromatase mRNA expression.


CONCLUSIONS
This study shows that melatonin inhibits aromatase activity and expression by regulating the gene expression of specific aromatase promoter regions. A possible mechanism for these effects would be the regulation by melatonin of intracellular cAMP levels, mediated by an inhibition of cyclooxygenase activity and expression.
Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain.
C
C
Martínez-Campa
A
A
González
M D
MD
Mediavilla
C
C
Alonso-González
V
V
Alvarez-García
E J
EJ
Sánchez-Barceló
S
S
Cos
D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000032:analysis; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis
D012333:RNA, Messenger; D000242:Cyclic AMP; D001141:Aromatase; D011451:Prostaglandin-Endoperoxide Synthases; D008550:Melatonin; D015232:Dinoprostone