Obesity promotes breast epithelium DNA damage in BRCA mutation carriers

Obesity is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated bodyweight is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear due to inconsistent findings from epidemiological studies and lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelium of BRCA mutation carriers is positively correlated with body mass index and with biomarkers of metabolic dysfunction. Additionally, RNA-sequencing reveals significant obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which impacts neighboring breast epithelial cells. We found that blockade of estrogen biosynthesis or estrogen receptor activity decreases DNA damage, whereas treatment with leptin or insulin increases DNA damage in BRCA heterozygous epithelial cells. Furthermore, we show that increased adiposity is associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1 +/- mice. Overall, our results provide mechanistic evidence in support of a link between bodyweight and breast cancer development in BRCA mutation carriers and suggests that maintaining a healthy bodyweight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population. One Sentence Summary Elevated bodyweight is positively associated with DNA damage in breast epithelium of BRCA mutation carriers ### Competing Interest Statement NMI receives consulting fees from Novartis, Pfizer, and Seattle Genetics; Honoraria from Curio Science, Cardinal Health, OncLive, IntrinsiQ Health; Research funding (to institution) from Novartis, SynDevRx, National Cancer Institute, American Cancer Society, Breast Cancer Research Foundation, and the Conquer Cancer Foundation. LED is a scientific advisor and holds equity in Mirimus Inc. and has received consulting fees and/or honoraria from Volastra Therapeutics, Revolution Medicines, Repare Therapeutics, Fog Pharma, and Frazier Healthcare Partners. BDH is a founder and consultant for Faeth Therapeutics.