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    Research Grants Awarded

    Breast Cancer And Diet: Role Of Cholesterol

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    Breast Cancer and Diet: Role of Cholesterol Diet and obesity are now considered important risk factors for cancer development. This is especially relevant for breast cancer development, where mammary ductal epithelial cells are essentially embedded in a mammary fat pad, which consists mainly of mammary adipocytes and fibroblastic stromal cells. The mammary fat pad serves both as a matrix and a source of essential growth factors/ nutrients for adjacent mammary epithelial cells, and can profoundly affect their tumorigenic potential. Epidemiologic studies have demonstrated that patients carrying tumors present with abnormal levels of LDL-cholesterol and HDL-cholesterol. Several studies have now directly suggested a role for cholesterol in tumorigenesis. However, very little is known about the relationship between lipoprotein and cholesterol metabolism and tumor development. Our hypothesis is that plasma cholesterol levels play a crucial role in the regulation of mammary tumor onset and progression. During mammary tumor development, tumor cholesterol requirements are very high compared to other tissues, since tumor cells divide much more rapidly than other cell types. Therefore, we will examine the i) regulation of plasma cholesterol (in the form of lipoproteins) and ii) the role of key cellular proteins involved in lipoprotein metabolism (namely SR-BI) during mammary tumor formation and lung metastasis. For this purpose, we will use an established mouse model of mammary tumorigenesis, namely MMTV-PyMT mice. These mice will be placed on a low-cholesterol or a high-cholesterol diet, and the onset and progression of mammary tumor formation and lung metastasis will be compared. We predict that mice on a high-cholesterol diet will show an increase in mammary tumor multiplicity and tumor burden, as well as metastasis. Finally, we will also examine the effects of dietary cholesterol in the context other genetic backgrounds that should affect cholesterol metabolism, such as in PyMT/SR-BI (-/-) mice. Interestingly, our unpublished preliminary studies indicate that a high-cholesterol diet does indeed function to promote mammary tumorigenesis in vivo. These studies should provide us with a clear understanding of the relationship between dietary intake of cholesterol, cholesterol metabolism, and breast cancer onset/progression.

    Lay Abstract:
    Breast Cancer and Diet: Role of Cholesterol Cancer is one of the leading causes of death in the Western world. Studies have now shown that diet can remarkably affect cancer onset and progression. Among the various factors to be known to play an important role, high cholesterol levels in the diet and in the blood are now recognized as potentially important risk factors that may promote tumor development, especially breast cancers. In our proposed studies, we will directly examine the cause-effect relationship between high levels of dietary cholesterol and mammary tumor development in a mouse model of human breast cancer. Moreover, we will perform a detailed analysis of cholesterol metabolism in i) mammary tumors and ii) in the blood of tumor-bearing animals. Finally, we will also determine whether certain gene products that are involved in the regulation of blood cholesterol can affect tumor development. For example, we will attempt to reduce tumor formation by genetically preventing cholesterol utilization by tumors.