The purpose of this K08 Mentored Clinical Scientist Development Award proposal is to describe the five year training, development and mentorship plan for Dr. Emily Gallagher, in addition to her research plans to understand the link between obesity, Type 2 diabetes and breast cancer, specifically by examining the effect of high circulating cholesterol on breast cancer progression. Dr. Gallagher received her MD with honors from the University College Dublin, Ireland. She trained clinically in Ireland before moving to New York and is Board Certified in Internal Medicine and Endocrinology. As a clinician, Dr. Gallagher recognized the importance of basic science research in advancing clinical medicine. She moved to the United States to develop her career as a clinician-scientist and began her research studying the mechanisms linking obesity and Type 2 diabetes with breast cancer as a fellow in 2010. She graduated from fellowship in 2012 and was promoted to Assistant Professor in the Department of Medicine at Mount Sinai School of Medicine and given her own lab space to develop her research into cholesterol and breast cancer. She spends 80% of her time conducting research and the remaining 20% of her time treating endocrinology patients, many of who are also oncology patients, giving her first hand experience of the growing number of patients with obesity and Type 2 diabetes with cancer and the need to understand the links between metabolic conditions and cancer to appropriately treat these patients. Dr. Gallagher's goals during the K08 Award period are to develop her skills in a core set of molecular biology techniques; broaden her knowledge of cancer biology and lipidology; form collaborations for future research projects and advance our understanding of the mechanisms linking elevated cholesterol and breast cancer. Dr. Gallagher's mentors, Drs. LeRoith, Parsons, and Ginsberg, individually have many years of successful mentoring experience and are all experts in their own areas of research. In addition to her mentors, Dr. Gallagher has succeeded in putting together a team of advisors in the fields of oncology and metabolism from Mount Sinai and Columbia University who will provide their support in specific aspects of the current project, her career progression and the development of future basic science and clinical research projects based on the results of the experiments described in this proposal. Furthermore, Mount Sinai School of Medicine offers all of the environmental support Dr. Gallagher needs to succeed in her research and overall career objectives. The proposed research project aims to examine the mechanisms linking obesity, Type 2 diabetes and increased breast cancer risk, in order to identify targets for therapies that will improve survival in these women. Elevated serum cholesterol is frequently seen in people with obesity and Type 2 diabetes. These patients may have elevated low density lipoprotein (LDL) or very low density lipoprotein (VLDL). These abnormal elevations in serum cholesterol have been associated with an increased risk of hormone receptor negative and Her2 overexpressing breast cancers and a poor prognosis in breast cancer patients. It is hypothesized that increased cholesterol delivery to breast cancers by VLDL and/or LDL is driving breast cancer growth and spread, particularly in breast cancers with high levels of the low-density lipoprotein receptor (LDLR) that mediates cholesterol uptake from VLDL and LDL. This cholesterol uptake may promote tumor growth by activating signaling pathways that promote survival and proliferation. In addition, cholesterol may be metabolized into biologically active metabolites (one of which is 25-hydroxycholesterol) that may promote tumor metastasis. Therefore, the research hypothesis for this proposal is that elevated circulating cholesterol in the form of VLDL or LDL cholesterol promotes breast cancer growth and metastasis by delivery of cholesterol to cancer cells via the LDLR. The main aims of Dr. Gallagher's proposed research are: (1) To determine if high circulating cholesterol promotes breast cancer growth directly by increased cholesterol uptake through the LDLR in estrogen receptor positive, hormone receptor negative and Her2 overexpressing breast cancers; (2) To examine if cholesterol uptake through the LDLR leads to activation of a particular signaling pathway in all breast cancer subtypes and if lowering serum lipid levels and silencing the LDLR on tumor cells prevents activation of this pathway; (3) To determine the role of the cholesterol metabolite 25-hydroxycholesterol on tumor growth and metastasis by targeting the enzymes involved in its formation and studying the effects of 25- hydroxycholesterol on intracellular signaling, cytokine expression and epithelial-to-mesenchymal transition. Through these studies Dr. Gallagher aims to advance the field of metabolism and cancer by understanding the role of cholesterol in different breast cancer subtypes. With the results of these studies and through her collaborators and advisors, she plans to develop translational projects to change clinical practice and appropriately treat patients with obesity, Type 2 diabetes and breast cancer. Her abilities, dedication and determination to succeed in her goals are recognized by the Dean and Chair of Medicine at Mount Sinai School of Medicine, as well as her mentors and advisors, who are all offering their support to help her successfully complete her project and become an independent investigator and expert in the field of metabolism and cancer.