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Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast

C Martínez-Campa1, A González, M D Mediavilla

  • 1Department of Physiology and Pharmacology, School of Medicine, University of Cantabria, 39011 Santander, Spain.

British Journal of Cancer
|September 24, 2009
PubMed
Abstract

Insights

Melatonin inhibits breast cancer growth by downregulating aromatase expression via specific promoter regions. This effect may involve regulating intracellular cyclic AMP (cAMP) and inhibiting cyclooxygenase (COX) activity.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Melatonin exhibits anti-breast cancer properties by modulating estrogen signaling pathways.
  • Melatonin is known to inhibit aromatase activity and expression, key factors in estrogen-dependent breast cancer.
  • Understanding melatonin's regulatory mechanisms on aromatase is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To investigate the specific aromatase promoter regions regulated by melatonin.
  • To evaluate melatonin's effect on cyclooxygenase (COX) enzymes and prostaglandin E2 (PGE2) production.
  • To determine if melatonin's impact on aromatase is mediated by intracellular cyclic adenosine monophosphate (cAMP) levels.

Main Methods:

  • Real-time RT-PCR was used to quantify total aromatase mRNA, specific aromatase promoter regions (pII, pI.3, pI.4), and cyclooxygenase (COX-1, COX-2) mRNA expression.
  • Prostaglandin E2 (PGE2) and cyclic adenosine monophosphate (cAMP) levels were measured using commercial assay kits.
  • MCF-7 breast cancer cells were utilized to assess the cellular effects of melatonin.

Main Results:

  • Melatonin significantly downregulated the gene expression of aromatase promoter regions pII, pI.3, and pI.4.
  • A low concentration of melatonin (1 nM) counteracted the stimulatory effect of tetradecanoyl phorbol acetate on PGE2 production and inhibited both COX-1 and COX-2 mRNA expression.
  • Melatonin (1 nM) induced a time-dependent decrease in intracellular cAMP formation, paralleling the reduction in aromatase mRNA expression.

Conclusions:

  • Melatonin inhibits aromatase activity and expression through the regulation of specific aromatase promoter regions.
  • A potential mechanism involves melatonin's regulation of intracellular cAMP levels, which is possibly mediated by the inhibition of cyclooxygenase activity and expression.
  • These findings elucidate novel pathways through which melatonin exerts its oncostatic effects in breast cancer.

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