Chemopreventive Role of Metformin during DMBA–induced Breast Carcinogenesis in MCF10A Cells through CYP1A1‐AhR Signaling Pathway

Abstract

Recent studies have established that metformin (MET), an oral hypoglycemic drug, possesses antioxidant activity and effective against different types of cancer. Although several postulated mechanisms were reported, the role of the cytochrome P450 1A1 (CYP1A1)‐aryl hydrocarbon receptor (AhR) signaling pathway in the protective effect of MET against breast cancer has not been reported before. Therefore, we examined the capacity of MET to inhibit CYP1A1 gene expression and DNA adducts formation in human breast cells MCF10A by dimethylbenz[a]anthracene (DMBA), a well‐known breast chemical carcinogen. Our results showed that DMBA‐induced DNA adduct was completely prevented by MET as evidenced by decrease in DNA repair genes and 8‐hydroxy‐2′‐deoxyguanosine level. Importantly, MET inhibited the induction of CYP1A1 mRNA, protein and activity levels by DMBA, suggesting a direct role of CYP1A1. Mechanistically, this was strongly correlated with MET ability to inhibit AhR‐dependent luciferase activity, but there was no effect on AhR activation, as evidenced by binding assay, suggesting that MET is not an AhR ligand. In conclusion, the present work provides the first evidence that MET inhibits the DMBA‐mediated carcinogenicity by inhibiting the expression of CYP1A1 through an AhR ligand‐independent mechanism. This work was supported by the Deanship of Scientific Research grant no. RGP‐VPP‐141.