Investigating The Role of Cholesterol Metabolism and Synthesis In Metastasis and Radiation Response In Aggressive Subtypes of Breast Cancer

<p>Aggressive breast cancers, triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC), metastasize at a high rate and are notoriously resistant to standard treatments. Research has shown diets high in cholesterol increase the incidence of aggressive breast cancers and pre-clinical research has shown cholesterol can fuel the growth of breast cancer in vivo. Studies at MD Anderson have shown that IBC patients taking cholesterol lowering drugs, statins, have improved survival outcomes, and also statins can improve the response to radiation in vitro. Furthermore, statins have been shown to target the cells with stem like-properties called cancer stem cells (CSCs) which are known to be important in the pathogenesis of aggressive breast cancers. However, the effects of statins specifically on TNBC metastasis and the mechanism of action have not been explored. Furthermore, the transporters of cholesterol, high-density (HDL) and very low-density (VLDL) lipoproteins, have not been studied extensively in aggressive breast cancers. Due to the associations with cholesterol and incidence of breast cancer and the work done with statins and IBC, I hypothesized reductions in intracellular cholesterol content by statins or HDL inhibits downstream signaling regulating metastasis and radiation response, altering cellular functions in cancer cells and immune cells. Here I show for the first time that statins can inhibit TNBC cell metastasis in vivo, and is dependent on FOXO3a activation, demonstrate a potential role for dyslipidemia in radiation sensitivity and survival among IBC patients, reveal miR-33a regulates HDL-induced radiation sensitivity in breast cancer, and mesenchymal stem cells (MSCs) and macrophages can influence each other to increase the tumor promoting influence of each on IBC cells which can be inhibited with statins.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Wolfe, Adam

Contributors dc:contributor

• Wendy Woodward
• Russell Broaddus
• Ann Klopp

• Cancer Stem Cell
• Inflammatory Breast Cancer
• Lipoprotein
• Triple-Negative Breast Cancer
• Cancer Biology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/601

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1643