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Characterization of a model of early-onset diet induced obesity and mammary tumorigenesis

By Charles W. Rehrer

Abstract

Obesity is a major health concern and a risk factor for increased tumor aggressiveness and mortality in premenopausal women. The recent epidemic of childhood obesity emphasizes a need to determine the influence of early increases in adiposity on cancer. To begin addressing this issue, we describe the characterization of an outbred rat model of early-onset diet induced obesity (DIO) and breast cancer. Weanling Sprague-Dawley rats were randomly placed on either a western or rat chow control diet. Animals on the western diet were divided into western obese and western lean groups based on percent fat mass. Western obese rats exhibited a significant 2-fold increase in fat mass, compared to western lean and rat chow animals. Obese rats had elevated levels of the circulating obesity comorbidity markers leptin, glucose, free fatty acids and triglycerides. When each rat group was treated with the carcinogen MNU, mammary tumors appeared sooner in obese and lean rats on the western diet compared to rat chow animals. Obese rats exhibited increased tumor multiplicity, a predominately invasive tumor phenotype and 42-fold lower ERα mRNA levels compared to the western lean and rat chow groups. As increasing evidence indicates the tissue microenvironment affects tumorigenesis, mammary glands and tumors were analyzed with the nonlinear optical imaging techniques, coherent anti-Stokes Raman scattering and second harmonic generation to image tumor cells, adipocytes and collagen fibrils. Multiphoton imaging of mammary stroma revealed a significant impact of diet and obesity on adipocyte and collagen 3-D structure, parameters not easily accessible by standard histology. Adipocyte size increased in obese and lean rats on the western diet, suggesting increased fat mass of obese rats results from adipocyte proliferation. Tumors from obese rats contained increased collagen levels that correlate with increased tumor aggressiveness. These studies begin to delineate the influence of diet and obesity on breast cancer by demonstrating a western diet at an early age results in earlier tumor onset, regardless of adiposity, whereas obesity significantly promotes tumor multiplicity and phenotype. This model represents a valuable tool for defining the relationship between early-onset adiposity and cancer, and for establishing strategies for the prevention of obesity-associated breast cancer

Topics: Molecular biology
Publisher: 'Purdue University (bepress)'
Year: 2010
OAI identifier: oai:docs.lib.purdue.edu:dissertations-10664
Provided by: Purdue E-Pubs
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