Resveratrol and its methoxy derivatives modulate the expression of estrogen metabolism enzymes in breast epithelial cells by AhR down-regulation

Mol Cell Biochem. 2017 Jan;425(1-2):169-179. doi: 10.1007/s11010-016-2871-2. Epub 2016 Nov 16.


Our earlier studies have shown that compared to resveratrol, its analogs with ortho-methoxy substituents exert stronger antiproliferative and proapoptotic activity. Since estrogens are considered the major risk factors of breast carcinogenesis, the aim of this study was to evaluate the effect of 3,4,2'-trimethoxy (3MS), 3,4,2',4'-tetramethoxy (4MS), and 3,4,2',4',6'-pentamethoxy (5MS) trans-stilbenes on the constitutive expression of the enzymes involved in estrogen metabolism, as well as receptors: AhR and HER2 in breast epithelial cell line MCF10A. The results showed different effect of resveratrol and its methoxy derivatives on the expression of genes encoding key enzymes of estrogen synthesis and catabolism. Resveratrol at the doses of 1 and 5 µmol/L increased the level of CYP19 transcript and protein level, while 5MS reduced mRNA transcript of both CYP19 and STS genes. Resveratrol and all its derivatives reduced also SULT1E1 mRNA transcript level. The reduced expression of AhR, CYP1A1, and 1B1 was also found as a result of treatment with these compounds. The most significant changes were found in the case of AhR. The most potent inhibitor of CYP1A1 and 1B1 genes expression was 5MS, which reduced the levels of mRNA transcript and protein of both CYPs from 31 to 89% of the initial levels. These results indicate that methoxy derivatives of resveratrol might be efficient modulators of estrogen metabolism. Moreover, the number of methoxy groups introduced to stilbene structure may play a certain role in this effect.

Keywords: AhR; Breast cancer; CYP450; Methoxy-trans-resveratrol; STS; SULT1E1.

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P-450 Enzyme System / genetics
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects*
  • Estrogens / biosynthesis*
  • Estrogens / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Receptors, Aryl Hydrocarbon / biosynthesis*
  • Receptors, Aryl Hydrocarbon / genetics
  • Resveratrol
  • Stilbenes / pharmacology*
  • Sulfotransferases / biosynthesis*
  • Sulfotransferases / genetics


  • AHR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Estrogens
  • Neoplasm Proteins
  • Receptors, Aryl Hydrocarbon
  • Stilbenes
  • Cytochrome P-450 Enzyme System
  • Sulfotransferases
  • estrone sulfotransferase
  • Resveratrol