The Anti-Tumor Effect of a High Caloric Diet in the PyMT Mouse Breast Cancer Model Is Initiated by an Increase in Metabolic Rate

Linda C Enns,Warren C Ladiges

doi:10.4236/jct.2012.325091

Abstract

Obesity is associated with an increased risk of mortality from certain types of cancer, including cancer of the breast. Because obesity is associated with multiple risk factors, however, the exact reasons remain unclear. The objective of this study was to determine which of the risk factors associated with obesity are related to enhanced tumor development. The MMTV-PyMT mouse model develops mammary tumors which share numerous characteristics with those of humans. We challenged these mice with a high fat/high carbohydrate, high caloric (HC) diet, and looked for relationships between enhanced primary tumor development and adiposity, various aspects of glucose homeostasis, and metabolic factors. The HC diet enhanced tumor progression in PyMT mice. While mice on the HC diet also developed increased adiposity, hyperglycemia and hyperinsulinemia, none of these risk factors was found to be associated with the observed increases in tumor growth. Rather, we found that while overall, tumor growth was enhanced in HC diet-fed mice compared to those maintained on a regular diet, it was attenuated in individuals by an HC diet-induced increase in metabolic rate and decrease in respiratory exchange ratio. Tumor size in HC diet-fed mice was directly related to p38 phosphorylation and Bcl-2 inhibition, and the degree of vascularization of these tumors was closely and indirectly related to the rate of mouse oxygen consumption. The data suggest that an increase in metabolic rate and oxygen consumption, induced by the introduction of a high caloric diet, has a protective effect against tumor growth by increasing the activity levels of the tumor suppressor p38 and decreasing the activity of the antiapoptoic protein Bcl-2, as well as by reducing hypoxia-induced tumor vascularization.

Highlights

With numerous studies documenting an increase in obesity worldwide [1], obesity and its associated diseases are rapidly becoming a central health problem of this century
The high caloric (HC) diet caused both PyMT mice and WT controls to accumulate fat over the course of the dietary challenge, the rate of fat accumulation was lower in the presence of tumors (Figure 1(a))
Metabolic syndrome is characterized by abdominal obesity, high blood glucose and insulin resistance, and high blood pressure

Summary

Introduction

With numerous studies documenting an increase in obesity worldwide [1], obesity and its associated diseases are rapidly becoming a central health problem of this century. In addition to being at increased risk of developing certain cancers compared to people who are lean, obese individuals have a higher likelihood of dying from those cancers once they occur [5]. This study was designed to determine which of these different risk factors could be associated with tumor growth in a high fat/high carbohydrate, high caloric (HC) diet-challenged mammary cancer mouse model, in an effort to assess the importance of these individual factors in their contribution to enhanced cancer progression. Transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/ enhancer (MMTV-PyMT) develop widespread transformation of the mammary epithelium and the production of multi- focal mammary adenocarcinomas, with secondary metastasis to the lungs [7]. We developed a population of transgenic (MMTV-PyMT)634Mul mice on a C57BL6/J background, a strain known to be obesity and diabetes

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