ABSTRACT Obesity is a leading cause of health disparities in the general population, being associated with increased risk of breast cancer, decreased response to treatment and higher rates of cancer-associated mortality. Women with a germline mutation in BRCA1 or BRCA2 have a 4-7-times increased risk of developing breast cancer compared to the general population. We have discovered that body mass index (BMI) and poor metabolic health is associated with more DNA damage in the non-tumor breast glands of BRCA1 and BRCA2 mutation carriers. DNA damage is credited for the development of cancer from non-cancer cells. In fact, our studies in mice demonstrate that more mice develop tumors when they are obese (compared to lean) and that these develop at a younger age. We now have evidence that having a mutation in BRCA may predispose to poor metabolic health, leading to a potential vicious cycle whereby increased cancer risk may be in part driven by detrimental effects of BRCA mutations in metabolic tissues, including the liver, adipose tissue, pancreas and muscle. We hypothesize that carrying a BRCA mutation leads to defects in mitochondria, the powerhouse of the cell, in metabolic tissues, leading to poor metabolic health and increased cancer risk. This study aims to: 1) Understand the mechanism of impaired metabolic health in mice with loss of Brca1 2) Determine if carrying a mutation in BRCA affects biomarkers of metabolic health in women These studies will determine whether additional follow up related to metabolic health should be considered after a BRCA diagnosis. By also exploring metabolic targets, this project has the potential to identify risk reduction strategies for BRCA mutation carriers for whom standard of care remains prophylactic surgery.

PROJECT NARRATIVE Mutations in the genes BRCA1 or BRCA2 increase the risk of breast and ovarian cancers, and we have found that having obesity or unhealthy metabolism increases damage to the cells of the breast and fallopian tube that can become cancerous. In mouse models, we discovered that having a mutation in BRCA leads to unhealthy metabolism which may contribute to cancer - this has not been shown before. A first step will be to understand which metabolic tissues are affected and whether this is also true for women, as this could help us understand why some women develop cancer and find ways of reducing their risk.