While many studies have shown that maternal weight and nutrition in pregnancy affects offspring's breast cancer risk, no studies have investigated the impact of paternal body weight on daughters' risk of this disease. Here, we show that diet-induced paternal overweight around the time of conception can epigenetically reprogram father's germ-line and modulate their daughters' birth weight and likelihood of developing breast cancer, using a mouse model. Increased body weight was associated with changes in the miRNA expression profile in paternal sperm. Daughters of overweight fathers had higher rates of carcinogen-induced mammary tumors which were associated with delayed mammary gland development and alterations in mammary miRNA expression. The hypoxia signaling pathway, targeted by miRNAs down-regulated in daughters of overweight fathers, was activated in their mammary tissues and tumors. This study provides evidence that paternal peri-conceptional body weight may affect daughters' mammary development and breast cancer risk and warrants further studies in other animal models and humans.
Bibliographical noteFunding Information:
We thank the following Lombardi Cancer Center Shared Resources (SR) for their assistance: Animal Model SR, Histopathology & Tissue SR and Genomics & Epigenomics SR. This study was supported by the American Cancer Society (pilot grant to S.D.A.), the Prevent Cancer Foundation (Research grant # 299045 to S.D.A.) and National Institutes of Health (1P30-CA51008). C.C.F. was supported by a scholarship from the Brazilian National Council for Scientific and Technological Development (CNPq;153478/2012-8).