title: Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells.
abstract: Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA-MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184±0.045 mM, 0.665±0.007 mM, 2.347±0.010 mM and 1.885±0.015 mM (mean± standard error). Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition) and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Lidong
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Chenghao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Tiansong
authors.initials: T
authors.lastname: Xia
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zha
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Shui
authors.initials: S
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010629:Phenformin / Q000494:pharmacology* / Q000627:therapeutic use; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D010629:Phenformin; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases