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

MatthewD Thompson, Clinton J. Grubbs, AnnM Bode, Joel M Reid, Renee McGovern, Philip S. Bernard, Inge J. Stijleman, Jeffrey E. Green, Christina Bennett, M. Margaret Juliana, Fariba Moeinpour, Vernon E. Steele, Ronald A. Lubet

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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 <sup>+</sup>) mammary cancers in rats, and (ii) MMTV-Neu/p53KO ER<sup>-</sup> (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 (C<inf>max</inf> 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.

Original languageEnglish (US)
Pages (from-to)231-239
Number of pages9
JournalCancer Prevention Research
Volume8
Issue number3
DOIs
StatePublished - Mar 1 2015

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Metformin
Carcinogenesis
Breast
Breast Neoplasms
Methylnitrosourea
AMP-Activated Protein Kinases
Estrogen Receptors
Diet
Biguanides
Weights and Measures
Incidence
Insulin-Like Growth Factor I
Area Under Curve
Epidemiologic Studies
Neoplasms
Pharmacokinetics
Clinical Trials
Insulin

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models. / Thompson, MatthewD; Grubbs, Clinton J.; Bode, AnnM; Reid, Joel M; McGovern, Renee; Bernard, Philip S.; Stijleman, Inge J.; Green, Jeffrey E.; Bennett, Christina; Juliana, M. Margaret; Moeinpour, Fariba; Steele, Vernon E.; Lubet, Ronald A.

In: Cancer Prevention Research, Vol. 8, No. 3, 01.03.2015, p. 231-239.

Research output: Contribution to journalArticle

Thompson, M, Grubbs, CJ, Bode, A, Reid, JM, McGovern, R, Bernard, PS, Stijleman, IJ, Green, JE, Bennett, C, Juliana, MM, Moeinpour, F, Steele, VE & Lubet, RA 2015, 'Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models', Cancer Prevention Research, vol. 8, no. 3, pp. 231-239. https://doi.org/10.1158/1940-6207.CAPR-14-0181-T
Thompson, MatthewD ; Grubbs, Clinton J. ; Bode, AnnM ; Reid, Joel M ; McGovern, Renee ; Bernard, Philip S. ; Stijleman, Inge J. ; Green, Jeffrey E. ; Bennett, Christina ; Juliana, M. Margaret ; Moeinpour, Fariba ; Steele, Vernon E. ; Lubet, Ronald A. / Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models. In: Cancer Prevention Research. 2015 ; Vol. 8, No. 3. pp. 231-239.
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