title: Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway.
abstract: Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in
  quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Zaid H
authors.initials: ZH
authors.lastname: Maayah
authors.affiliation: Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Hazem
authors.initials: H
authors.lastname: Ghebeh
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Abdulqader A
authors.initials: AA
authors.lastname: Alhaider
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
authors.affiliation: Department of Environmental Toxicology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Soshilov
authors.affiliation: Department of Environmental Toxicology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Mushtaq Ahmad
authors.initials: MA
authors.lastname: Ansari
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: hkorashy@ksu.edu.sa.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Korashy
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D063646:Carcinogenesis / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000378:metabolism; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C059444:7,12-dimethylbenz(a)anthracene-DNA adduct; D016588:Anticarcinogenic Agents; D002273:Carcinogens; D018736:DNA Adducts; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C024829:8-hydroxyguanine; D015127:9,10-Dimethyl-1,2-benzanthracene; D006147:Guanine; D008687:Metformin; D019363:Cytochrome P-450 CYP1A1; D016660:NAD(P)H Dehydrogenase (Quinone)
keywords: AhR; Breast cancer; Cytochrome P4501A1; DNA damage; MCF10A cells; Metformin