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. 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

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Free PMC article

Lack of Effect of Metformin on Mammary Carcinogenesis in Nondiabetic Rat and Mouse Models

Matthew D Thompson et al. Cancer Prev Res (Phila). .
Free PMC article

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.

Conflict of interest statement

There is no Conflict of Interest with any Authors.

Figures

Figure 1
Figure 1. Effects of Metformin on the Development of MNU-Induced ER+Mammary Cancers
Female Sprague-Dawley rats were administered MNU at 50 days of age. Rats were administered daily metformin (150 or 50 mg/kg BW/day, by gavage) beginning 5 days after MNU. (A) Development of Palpable Cancers. Rats were examined 2×/week for palpable cancer development. Differences in cancer latency were not significantly different (P>.05). (B) Effects of metformin on cancer multiplicity. (C) Effects of metformin on final cancer weights. Tumors from individual rats were weighed at the termination of the study (140 days post MNU). The cancer weights were not significantly higher in the groups treated with metformin when compared to control rats.
Figure 2
Figure 2. Effects of Metformin on the Development of Mammary Carcinomas in MMTV-Neu/P53KO mice
Weanling mice were characterized for the presence both the MMTV-Neu transgene and the KO of one copy of the tumor suppressor gene p53. Mice were placed on control diet or diet containing 1500 mg/kg metformin at 60 days of age. Metformin did not significantly increase survival (P<.05) (A), and also did not impact incidence, multiplicity, (B), or cancer weight (C).
Figure 3
Figure 3. Effects of Metformin on Expression of Multiple Biomarkers Employing IHC
Rats bearing MNU-Induced cancers were treated with vehicle or metformin (150 mg/kg BW/day) for a period of 7 days. At that time, rats were sacrificed and tumors removed. Tissue slices were prepared and stained as described in Material and Methods. Representative staining is shown. (A) Shows alterations of expression in the various phosphorylated proteins in control mammary tumors following short term metformin exposure; (B) Shows IHC slides staining for the various phosphoproteins, DAPI and a merged image.
Figure 3
Figure 3. Effects of Metformin on Expression of Multiple Biomarkers Employing IHC
Rats bearing MNU-Induced cancers were treated with vehicle or metformin (150 mg/kg BW/day) for a period of 7 days. At that time, rats were sacrificed and tumors removed. Tissue slices were prepared and stained as described in Material and Methods. Representative staining is shown. (A) Shows alterations of expression in the various phosphorylated proteins in control mammary tumors following short term metformin exposure; (B) Shows IHC slides staining for the various phosphoproteins, DAPI and a merged image.
Figure 4
Figure 4. Effects of Metformin on Expression of Proliferation Related Biomarkers
Rats were treated as described in Materials and Methods. Both expression of proliferation related genes and Ki67 values were determined in formalin-fixed samples. (A) Effects of metformin and a positive control (tamoxifen) on proliferation index in mammary cancers. Results are based on counting at least 2,000 cells for each of the tumors. The Ki67 labeling index was significantly increased in cancers treated with metformin and decreased in cancers treated with tamoxifen (P<.05) when compared with controls. (B) Effects of metformin and tamoxifen on expression of proliferation related genes.

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