Obesity, hyperinsulinemia and breast cancer: novel targets and a novel role for metformin.
The relationship between obesity, metabolic syndrome, diabetes and cancer has been recognized for many years. Multiple studies conducted in the last 20 years have identified molecular mechanisms responsible for this phenomenon. Elucidation of the important role of insulin, IGF receptor, mTOR and AMP-activated protein kinase in breast cancer biology has led to the development and subsequent clinical evaluation of novel targeted therapies, including IGF-1 receptor-specific antibodies or tyrosine kinase inhibitors and inhibitors of mTOR. There is also a growing interest in the use of metformin, which has been shown to possess antitumor activity resulting from activation of AMP-activated protein kinase and subsequent inhibiton of mTOR, as well as from decreased circulating insulin levels. Metformin has been shown to inhibit proliferation, invasion and angiogenesis of neoplastic cells and to overcome resistance of breast cancer to chemotherapy, hormonal therapy and HER2 inhibition. Recently, metformin has been demonstrated to inhibit breast cancer stem cell growth and to synergize with chemotherapy in suppression of tumor growth and prolongation of survival of breast tumor-bearing animals. Several currently ongoing Phase II and III clinical studies are evaluating the therapeutic efficacy of metformin in the treatment of early and advanced breast cancer patients.
Wysocki
Piotr J
PJ
Department of Chemotherapy, Greater Poland Cancer Center, University of Medical Sciences, Poznan, Poland. pwysocki@plusnet.pl
Wierusz-Wysocka
Bogna
B
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000188:drug therapy / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use*; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013002:Somatomedins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D055372:AMP-Activated Protein Kinases; D052242:Adiponectin; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008687:Metformin; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D013002:Somatomedins; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human