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 to sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in non-diabetic women, the efficacy of metformin in non-diabetic 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: (1) methylnitrosourea (MNU)-induced ER+ mammary cancers in rats, and (2) MMTV-Neu/P53KO ER- mammary cancers in mice. In the MNU rat model, metformin dosing (150 or 50 mg/Kg BW/day, by gavage) was ineffective in decreasing mammary cancer multiplicity, latency, or weight. Pharmacokinetic studies of metformin (150 mg/kg BW/day, by gavage) yielded plasma levels (Cmax and AUC) higher than humans taking 1.5 g/day. In rats bearing small palpable mammary cancers, short-term metformin (150 mg/kg BW/day) 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 (1500 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 non-diabetic populations.

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

“…In contrast to our findings, a limited number of rodent studies have suggested that metformin does not affect mammary carcinogenesis (10,11). However, there are key differences in study design between our study and these previous reports that include variations in rodent age at initiation with MNU, diet, and dosage of metformin.…”

“…A number of preclinical studies of mammary carcinogenesis and in vitro studies using breast cancer cell lines are consistent with this assertion of metformin's beneficial effects (4-9). Even so, other preclinical studies of mammary carcinogenic models failed to see any effect of metformin when the animals were fed a low fat diet and exhibited no metabolic dysfunction (10,11). These conflicting reports suggest that there may be specific factors and metabolic conditions that confer a tumor's sensitivity to metformin.…”

“…The fact that metformin had little to no effect in preclinical studies in non-diabetic animals on a low fat diet would suggest the systemic effects of metformin are relevant (10,11). Observations that the effects of metformin are evident or more pronounced in obese or HF fed models (12,13) would support this notion.…”

Effects of Metformin, Buformin, and Phenformin on the Post-Initiation Stage of Chemically Induced Mammary Carcinogenesis in the Rat

“…A lack of effect for metformin in non-diabetic preclinical rodent models of breast cancer has been recently reported (37). These findings are confirmed and extended in this work by evaluation of additional biguanides.…”

Repurposing old drugs to chemoprevention: the case of metformin

“…Two of these studies showed an increase in female animal life span independent of effect on tumor incidence 31, 33 , although in a study by Anisimov et al, the 4.4% increase in mean life span in females was counterbalanced by a 13.4% decrease in male animal mean life spans 34 . A recent study using both an ER-positive rat carcinogenesis model and Neu+/p53 knockout mice showed no effect of metformin administered at doses achievable in human beings 36 . Of note, the tumor burden and proliferation index trended toward increases with metformin treatment, the latter reaching statistical significance.…”