Abstract LB-244: Paternal obesity alters daughters' mammary gland development and increases markers of breast cancer risk in a mouse model

Introduction: While several epidemiologic and animal studies indicate that maternal nutrition and body weight during pregnancy lead to reprogramming of breast cancer risk in the offspring, no studies have investigated the impact of fathers’ obesity or dietary habits on offspring9s breast cancer risk. The goal of the current study is to investigate whether peri-conceptional paternal obesity can epigenetically reprogram father9s germ-line and increase their daughters’ likelihood of developing breast cancer, using a carcinogen-induced mouse model of this disease. Methodology: Male mice were fed a control diet or obesity-inducing diet from weaning until sexual maturity; at this point, all males were switched to the control diet and housed together with female rats reared on control diet. Once a vaginal plug was detected, males were removed from female cages and euthanized for sperm collection. Pregnant dams were fed the control diet for the extent of pregnancy and after giving birth. Pups were weaned on postnatal day (PND)21 and fed the control diet throughout the experiment. Offspring9s body weight was determined shortly after birth and at weaning. A subset of female offspring was euthanized on PND50 for mammary tissue harvesting. Mammary gland whole-mounts harvested on PND50 were processed and the number of TEBs and ductal elongation blindly examined. Using miRNA arrays, we also investigated whether misregulation of miRNAs expression is involved in mediating the effects of paternal obesity on offspring9s mammary gland morphology. Another subset of female offspring was treated with 9,12-dimethylbenz[a]anthracene to induce mammary tumors and is currently being monitored. Results: We found that, compared to control offspring, the offspring of obese fathers had higher birth weight (p=0.02). Birth weight has been positively associated with breast cancer risk in epidemiologic and animal studies. Body weight of daughters (p=0.03), but not sons (p=0.6), of obese fathers were also higher at weaning. Daughters of obese fathers had higher numbers of terminal end buds (TEBs; p=0.03) _ which are targets for malignant transformation and markers of increased breast cancer risk_ in their mammary glands compared to control daughters. Mammary gland ductal elongation (p=0.004) in daughters of obese fathers was also increased. In addition, we found that paternal obesity led to changes in the miRNA expression profile in their sperm. Paternal obesity was also associated with changes in miRNA expression in daughters’ mammary tissue. Conclusions:This study provides critical evidence that fathers’ body weight around conception affects not only their daughters’ body weight at birth and weaning, but it also leads to changes in their daughters’ mammary gland development and miRNA expression profile, and likely their mammary cancer risk. Studies to confirm whether these findings are causally related to increased mammary cancer risk in daughters of obese fathers are currently underway. Citation Format: Chao Yin, Idalia Cruz, Leena Hilakivi-Clarke, Sonia M. de Assis. Paternal obesity alters daughters9 mammary gland development and increases markers of breast cancer risk in a mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-244. doi:10.1158/1538-7445.AM2014-LB-244