Date of Award

1-1-2012

Document Type

Campus Access Dissertation

Department

Exercise Science

First Advisor

J. Mark Davis

Abstract

Breast cancer (BrCa) is the second most commonly diagnosed cancer and the leading cause of cancer related death in women in the United States. A substantial proportion of breast cancers are incited, aggravated or caused by lifestyle factors. For example, consumption of high fat diets (HFD), as well as diets low in fruits and vegetables, is associated with enhanced BrCa risk. MCP-1 is an important chemoattractant released from the tumor microenvironment that contributes to the accumulation of tumor associated macrophages (TAMs). TAMs enhance mammary tumor growth by promoting chronic inflammation, tumor cell invasion, angiogenesis and metastasis. Quercetin is a flavonol present in several plant based foods with anti-inflammatory, anti-obesogenic and anti-carcinogenic actions; however, these effects of quercetin have not yet been explored in a mouse model of BrCa. The purpose of this study was to examine the benefits of quercetin in the attenuation of tumorigenesis and HFD-enhanced tumorigenesis in the C3(1)/SV40Tag mouse model of BrCa, and to begin to delineate if these effects are mediated by reductions in MCP-1 and TAMs. Specific Aim 1 employed a dose-response paradigm and established the 0.2% dose of quercetin to be the most effective for reducing tumor growth. However, these benefits of quercetin were independent of any changes in MCP-1 or TAMs within the tumor microenvironment. Specific Aim 2 extended these findings and investigated the therapeutic potential of quercetin on HFD-enhanced BrCa. Quercetin offset the HFD-induced increase in tumorigenesis; tumor number and volume were reduced and inflammatory factors within the tumor trended to be decreased. However, these benefits did not appear to be due to reductions in body weight, adipose tissue inflammation, circulating leptin or circulating MCP-1. In Specific Aim 3 an inhibitor of MCP-1, bindarit, was used to determine if tumor growth in C3(1)/SV40Tag mice is influenced by MCP-1. Despite decreasing MCP-1 and pro-tumor inflammation, bindarit did not reduce tumor growth. In summary, quercetin reduced mammary tumorigenesis in both the normal and HFD-enhanced C3(1)/SV40Tag mouse model of BrCa. However, treatment with an MCP-1 inhibitor had no effect indicating that tumor growth in C3(1)/SV40Tag mice occurs by mechanisms independent of MCP-1 and TAMs.

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