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Reversal Effects of Genistein and (−)‐Epigallocatechin‐3‐Gallate on Repression of BRCA‐1 Expression in Human Breast Cancer Cells with Activated AhR
Author(s) -
Selmin Ornella I,
Papoutsis Andreas J,
Romagnolo Donato F
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.42.6
Subject(s) - genistein , chromatin immunoprecipitation , cancer research , estrogen receptor , breast cancer , aryl hydrocarbon receptor , medicine , carcinogen , chemistry , cancer , gene silencing , endocrinology , biology , gene expression , gene , transcription factor , biochemistry , promoter
Sporadic breast cancers, which represent the vast majority (~90%) of breast tumor cases, do not have mutations in the tumor suppressor gene, BRCA‐1 but have absent or markedly reduced levels of BRCA‐1 similar to those observed in hereditary BRCA‐1 tumors. Therefore, understanding the non‐mutational mechanisms that contribute to silencing of BRCA‐1 has important implications for the prevention of both hereditary and sporadic breast tumors. Agonists of the aromatic hydrocarbon receptor (AhR) are ubiquitous in the environment and include dietary compounds, metabolites of fatty acids, industrial pollution, and photoproducts generated in the skin from ultraviolet radiation. In cultured estrogen‐receptor (ER)α‐positive MCF‐7 breast cancer cells, we found that the BRCA‐1 gene is a molecular target for activation by estradiol. In contrast, the cotreatment with equimolar (10 nM) concentrations of the prototype AhR‐ligand 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD) repressed by 50% estrogen‐induced BRCA‐1 protein expression. The post‐treatment with the soy isoflavone genistein and tea (−)‐epigallocatechin‐3‐gallate (EGCG) at physiological doses (1 μM) rescued within 24 to 48 h BRCA‐1 protein expression to levels ~2.0 to 3.0‐fold higher than those measured in cells treated with estradiol. In ERα‐negative/AhR‐overexpressing UACC‐3199 breast cancer cells, genistein increased BRCA‐1 expression in a dose‐dependent fashion (1nM to 1μM). In chromatin immunoprecipitation assays with MCF‐7 cells, the post‐treatment with genistein and EGCG antagonized the TCDD‐induced recruitment of DNA‐methyl transferase‐1 (DNMT‐1) enzyme at the BRCA‐1 gene. These results suggest the involvement of epigenetic mechanisms in the reactivation of BRCA‐1 expression and preventative effects of genistein and EGCG against breast tumorigenesis associated with exposure to AhR carcinogens. Support or Funding Information This work was supported by grants from the Arizona Biomedical Research Commission (QSR14082995), the US Department of Defense Breast Cancer Program (BC134119), and Soy Health Research Foundation.