Short-term consumption of the modified standard American diet perturbed the metabolic balance and altered DNA damage in MMTV-PyMT transgenic mice

TL;DR

A modified American diet increased weight and DNA damage in mice with breast cancer, potentially making tumors more aggressive.

Contribution

The study introduces a diet model that reflects typical American eating habits and links it to breast cancer progression.

Findings

The SAD2 diet caused increased body weight and adiposity in mice.

The diet led to earlier tumor initiation and decreased survival in mice.

The diet increased oxidative DNA damage and AGEs, along with Foxm1 and Glut1 expression in tumors.

Abstract

Risk factors for breast cancer include obesity and hyperglycemia, which are associated with poor survival. Previous studies have used high-fat diets (HFDs) or Western-style diets to model dietary influences on breast cancer progression. However, these diets do not reflect the energy-dense, nutrient-poor diets that Americans typically consume. To address this gap in our understanding of the interplay between diet and breast cancer progression, we examined the effects of a modified standard American diet (SAD2) on mammary tumorigenesis in the MMTV-PyMT transgenic murine model and their FVB/N controls.

MMTV-PyMT and FVB/N mice were fed normal chow or the experimental diet SAD2 for up to 12 weeks. We evaluated body weight, blood glucose, adiposity, cytokine, and tumor characteristics to measure SAD2 diet-induced changes in breast tumor development.

Increased body weight and adiposity were observed in MMTV SAD2-treated mice, consistent with the findings of shorter-term HFD studies. The SAD2 diet also resulted in earlier tumor initiation and progression and decreased survival in the SAD2-fed mice. While only modest changes were observed in circulating cytokines and metabolic parameters, the SAD2 tumors presented significant changes in oxidative DNA damage and advanced glycation end products (AGEs). These changes coincided with increases in the oncogenic transcription factor Foxm1 and the expression of Glut1. Both proteins are elevated in breast cancer patient samples but have not yet been linked to diet-induced effects.

Using SAD2, we demonstrated that an American-style diet increased weight and adiposity while promoting the accumulation of oxidative DNA damage and AGEs and the expression of oncogenic Foxm1 within a relatively short diet interval. These data suggest that the SAD2 diet may offer insight into mechanisms that promote breast cancer aggressiveness and resistance to therapy.

The online version contains supplementary material available at 10.1186/s13058-025-02075-w.

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