Obesity accelerates mammary carcinogenesis in a rat model of polygenic obesity susceptibility
Date
2015
Authors
Matthews, Shawna Beth, author
Thompson, Henry J., advisor
Henry, Charles, committee member
Hickey, Matthew, committee member
Melby, Christopher, committee member
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Abstract
Given the ongoing obesity epidemic, in which more women in the US are overweight or obese than are lean, the impact of obesity on the development of breast cancer is an important public health concern. Obese women with breast cancer generally have larger tumors and poorer prognosis than lean women with breast cancer. In an effort to deconstruct the biological mechanisms that link obesity and breast cancer, we have developed a novel rat model with high relevance to the polygenic development of obesity and breast cancer in humans. These rats have differing susceptibility to obesity when fed a diet of similar macronutrient composition as that consumed by the average American woman. Diet susceptible (DS) rats rapidly accumulate excess body fat and display metabolic perturbations, including resistance to insulin and leptin, which normally provide "stop eating" anorexigenic cues. In contrast, diet resistant (DR) rats remain lean despite being fed the same diet. Findings from experiments conducted in our novel rat model have provided several critical pieces of information. When DR and DS rats were treated with a chemical carcinogen, DS rats displayed markedly accelerated mammary cancer formation compared to DR rats, including higher cancer incidence, multiplicity, and tumor burden, in conjunction with reduced cancer latency. The larger tumor mass in DS rats was found to be attributable to higher growth rates in DS vs. DR tumors, due to a combination of accelerated cell cycle progression and reduced apoptotic efficiency. Importantly, DS rats tended to develop more tumors that were negative for sex hormone receptor expression, a subtype of breast cancer with high rates of breast cancer mortality. This observation was corroborated by an endocrine ablation experiment, i.e., bilateral ovariectomy. Removal of the ovaries puts a strong selection pressure on expansion of cell populations that can grow in the absence of high circulating levels of sex hormones. In addition to removal of the primary source of circulating sex hormones, several experiments failed to provide evidence in support of peripheral production of estrogen by adipose tissue. In spite of the lack of estrogen at the host systemic and local (mammary gland) level, ovariectomized DS rats displayed elevated cancer multiplicity and sum tumor weight compared to ovariectomized DR rats, indicating that obesity in DS rats promotes the growth of cancer cells in an estrogen-independent manner. Clinically, chronic inflammation in adipose tissue as a consequence of obesity has been shown to create a permissive environment for the development of breast cancer. While DS rats display evidence of heightened fat storage in the form of adipocyte hypertrophy, there was no evidence of inflammation accompanying this hypertrophy in the rat mammary gland in the current studies. Thus, peripheral production of estrogen by fat tissue and chronic inflammation in fat tissue—two of the mainstream mechanisms proposed to link excess fat and breast cancer—do not appear to be obligatory biological processes for the effect of obesity on the increased cancer response in DS rats in our model. These findings suggest that our novel rat model represents a preclinical tool that facilitates investigation of mechanisms beyond those currently considered to link obesity to carcinogenesis of the breast. Breast cancer is a highly heterogeneous disease, and the integrated rat model reported herein is a tool that complements monogenic models of obesity and breast cancer in an effort to deconstruct the complex problem of breast cancer in clinical subpopulations whose disease is not explained via traditional mechanisms.
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Subject
breast cancer
obesity
prevention
rat