Bhardwaj, Priya Iyengar, Neil M. Zahid, Heba Carter, Katharine M. Byun, Dong Jun Choi, Man Ho Sun, Qi Savenkov, Oleksandr Louka, Charalambia Liu, Catherine Piloco, Phoebe Acosta, Monica Bareja, Rohan Elemento, Olivier Foronda, Miguel Dow, Lukas E. Oshchepkova, Sofya Giri, Dilip D. Pollak, Michael Zhou, Xi Kathy Hopkins, Benjamin D. Laughney, Ashley M. Frey, Melissa K. Ellenson, Lora Hedrick Morrow, Monica Spector, Jason A. Cantley, Lewis C. Brown, Kristy A. 2024-01-19T10:03:28Z 2024-01-19T10:03:28Z 2023-04-06 2023-02 1946-6234 https://pubs.kist.re.kr/handle/201004/113998 Obesity, defined as a body mass index (BMI) >= 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was 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 elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population. English American Association for the Advancement of Science Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2 Article 10.1126/scitranslmed.ade1857 1 Science Translational Medicine, v.15, no.684 Science Translational Medicine 15 684 N scie scopus 000949044100003 2-s2.0-85148551082 Cell Biology Medicine, Research & Experimental Cell Biology Research & Experimental Medicine Article OVARIAN-CANCER RISKS AROMATASE EXPRESSION GROWTH-STIMULATION GENE METFORMIN TISSUE CELLS INFLAMMATION SUSCEPTIBILITY OOPHORECTOMY