Metformin Protects against 7, 12‐Dimethylbenz[a]anthracene‐Induced Breast Cancer Initiation and Adduct Formation In Vivo Rat Model Through CYP1A1/CYP1B1 Pathway

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. In that, a study from our laboratory showed that MET protected against 7, 12‐dimethylbenz[a]anthracene (DMBA)‐induced breast carcinogenesis in vitro human non‐cancerous epithelial breast cells (MCF10A). However, whether MET can protect against breast cancer initiation in vivo rat model has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET against DMBA‐induced rat breast carcinogenesis and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1/1B1 pathway. In this regard, treatment of rat with DMBA (25 mg/kg) induced initiation of breast carcinogenesis in rat as evidenced by changes in biochemical and histopathological analysis. Importantly, the protective effect of MET against DMBA‐induced breast carcinogenesis was supported by the capability of MET (500 mg/kg) to restore the induction of the mRNA and protein expression levels of several DNA repair genes ( OGG1, XRCC1), and the level of 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG), a DNA damage marker. In addition, MET was able to restore DMBA‐mediated changes in the gene expression of apoptotic (caspase‐3 and BAX) and inflammatory (TNF‐α and IL‐6) mediators. Interestingly, these changes were associated with proportional decrease in DMBA‐induced CYP1A1 and CYP1B1 gene expression. In conclusion, the present work provides the first evidence that MET protects against DMBA‐iduced rat breast carcinogenesis by inhibiting DNA adduct formation, inducing apoptosis and inhibiting the expression of CYP1A1/CYP1B1 pathway. Support or Funding Information This Project was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Kingdom of Saudi Arabia, Award Number (12‐MED3131‐02)