Hypercholesterolemia as a Modifier of the Tumor Microenvironment in Breast Cancer
Abstract
Breast cancer continues to be the most commonly diagnosed cancer in women and is the second highest cause of cancer deaths. Thus, notwithstanding the importance of developing new and effective therapeutics, there is a major interest in defining breast cancer risk factors and exploiting this information to develop chemopreventive and lifestyle modification strategies that can help to reduce the burden of this disease. It is significant therefore that hypercholesterolemia and increased consumption of cholesterol have emerged as robust independent risk factors for breast cancer, although the biochemical mechanisms underlying this association are unclear. Thus, identifying the mechanisms linking hypercholesterolemia to breast cancer risk and the validation of strategies to mitigate the pathological effect of cholesterol in this disease are the primary objectives of this project. Considering contemporary insights from the cardiovascular system and in ocular diseases, we propose to test the hypothesis that hypercholesterolemia increases tumor macrophage content and alters the inflammatory activity of tumor-associated macrophages in a manner that facilitates tumor growth and progression. It is anticipated that at the conclusion of our studies, we will have (1) identified the mechanistic links between hypercholesterolemia and breast cancer pathogenesis, (2) established the utility of using cholesterol-lowering drugs and inhibitors of the inflammasome in breast cancer, and (3) defined the inflammatory program(s) by which cholesterol exerts its pathological effects. These important issues will be addressed in studies outlined in three aims that together constitute the blueprint for an integrated project that will inform near-term clinical evaluation. The results of this work will address the Breast Cancer Research Program (BCRP) overarching challenge of preventing breast cancer by highlighting the utility of lowering cholesterol as a breast cancer prevention strategy. Furthermore, our studies directed at assessing the role of hypercholesterolemia and inflammation in breast cancer pathogenesis will address the BCRP overarching challenge of identifying what drives breast cancer progression and identifying strategies to stop it. Insights from this proposal may also enable the identification and validation of biomarkers that can be used to stratify risk or inform retrospective epidemiological studies of cholesterol and cancer risk.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610656
Entities
People
- Donald P McDonnell
Organizations
- Duke University
- United States Army