title: Molecular pathways: preclinical models and clinical trials with metformin in breast cancer.
abstract: Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-of-opportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy.
authors.affiliation: Author's Affiliation: Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas athompson1@mdanderson.org.
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008954:Models, Biological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D008687:Metformin; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases