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Cancer Prev Res (Phila). 2015 Mar;8(3):231-9. doi: 10.1158/1940-6207.CAPR-14-0181-T. Epub 2015 Feb 13.

Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models.

Author information

1
National Cancer Institute, Bethesda, Maryland.
2
University of Alabama at Birmingham, Birmingham, Alabama. clintongrubbs@uabmc.edu.
3
Hormel Institute, University of Minnesota, Austin, Minnesota.
4
Mayo Clinic Cancer Center, Rochester, Minnesota.
5
Huntsman Cancer Institute, Salt Lake City, Utah.
6
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland.
7
University of Alabama at Birmingham, Birmingham, Alabama.
8
CARDG, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland.

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.

PMID:
25681088
PMCID:
PMC4355096
DOI:
10.1158/1940-6207.CAPR-14-0181-T
[Indexed for MEDLINE]
Free PMC Article

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