title: Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models.
abstract: Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared with sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK (AMP-activated protein kinase) and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in nondiabetic women, the efficacy of metformin in nondiabetic rat and mouse mammary cancer models was evaluated. Metformin was administered by gavage or in the diet, at a human equivalent dose, in standard mammary cancer models: (i) methylnitrosourea (MNU)-induced estrogen receptor-positive (ER(+)) mammary cancers in rats, and (ii) MMTV-Neu/p53KO ER(-) (estrogen receptor-negative) mammary cancers in mice. In the MNU rat model, metformin dosing (150 or 50 mg/kg BW/d, by gavage) was ineffective in decreasing mammary cancer multiplicity, latency, or weight. Pharmacokinetic studies of metformin (150 mg/kg BW/d, by gavage) yielded plasma levels (Cmax and AUC) higher than humans taking 1.5 g/d. In rats bearing small palpable mammary cancers, short-term metformin (150 mg/kg BW/d) treatment increased levels of phospho-AMPK and phospho-p53 (Ser20), but failed to reduce Ki67 labeling or expression of proliferation-related genes. In the mouse model, dietary metformin (1,500 mg/kg diet) did not alter final cancer incidence, multiplicity, or weight. Metformin did not prevent mammary carcinogenesis in two mammary cancer models, raising questions about metformin efficacy in breast cancer in nondiabetic populations.
authors: National Cancer Institute, Bethesda, Maryland.
authors: Matthew D
authors: MD
authors: Thompson
authors: University of Alabama at Birmingham, Birmingham, Alabama. clintongrubbs@uabmc.edu.
authors: Clinton J
authors: CJ
authors: Grubbs
authors: Hormel Institute, University of Minnesota, Austin, Minnesota.
authors: Ann M
authors: AM
authors: Bode
authors: Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Joel M
authors: JM
authors: Reid
authors: Mayo Clinic Cancer Center, Rochester, Minnesota.
authors: Renee
authors: R
authors: McGovern
authors: Huntsman Cancer Institute, Salt Lake City, Utah.
authors: Philip S
authors: PS
authors: Bernard
authors: Huntsman Cancer Institute, Salt Lake City, Utah.
authors: Inge J
authors: IJ
authors: Stijleman
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors: Jeffrey E
authors: JE
authors: Green
authors: Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland.
authors: Christina
authors: C
authors: Bennett
authors: University of Alabama at Birmingham, Birmingham, Alabama.
authors: M Margaret
authors: MM
authors: Juliana
authors: University of Alabama at Birmingham, Birmingham, Alabama.
authors: Fariba
authors: F
authors: Moeinpour
authors: CARDG, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
authors: Vernon E
authors: VE
authors: Steele
authors: CARDG, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.
authors: Ronald A
authors: RA
authors: Lubet
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D000477:Alkylating Agents; D014408:Biomarkers, Tumor; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D008770:Methylnitrosourea; D008687:Metformin