Abstract LB-301: Paternal overweight leads to reprogramming of daughters’ breast cancer risk in a mouse model
Authors: Castilho Fontelles Camile , Carney Elissa , Clarke Johan , Nguyen Nguyen , Yin Chao , Jin Lu , Hilakivi-Clarke Leena , Prates Ong Thomas , Cheng Zuolin , Fu Yi , Wang Yue , De Assis Sonia M. 
Published: July 2016

Background: Obesity and overweight are known to induce epigenetic changes. Acquired epigenetic traits have been shown to be transmitted from parents to offspring via the germ-line (eggs and sperm). Maternal weight and nutrition in pregnancy lead to reprogramming of the mammary gland tissue and breast cancer risk in the offspring, yet no studies have investigated the impact of fathers’ body weight on offspring's risk of this disease. Here we investigated whether paternal overweight can epigenetically reprogram father's germ-line and increase daughters’ likelihood of developing breast cancer, using a mouse model.

Methods: Male mice were fed control or obesity-inducing diets from weaning until sexual maturity; at this point, males were housed together with female mice reared on control diet. Once a vaginal plug was detected, males were euthanized for sperm collection. Pregnant dams were fed the control diet throughout pregnancy and after giving birth. Pups were fed the control diet throughout the experiment. A subset of female offspring was euthanized for mammary tissue harvesting. Another female offspring sub-set was treated with 9,12-dimethylbenz[a]anthracene (DMBA) to induce mammary tumors.

Results: We found that overweight in male mice alters their sperm epigenome, including the miRNA expression profile and DNA methylation patterns. We also observed that, compared to control offspring, the female offspring of overweight fathers had higher birth weight (p = 0.013).This increase in body weight persisted through early adulthood but disappeared as animals aged (p = 0.6). The mammary tissue of overweight fathers’ offspring had higher numbers of undifferentiated structures (terminal end buds; TEBs; p = 0.017) and ductal elongation (p = 0.004) compared to control daughters. In addition, their mammary miRNA expression profile was altered with some of the same changes observed in fathers. These changes in normal mammary tissue were associated with higher rates of DMBA-induced mammary tumors (p = 0.02) in daughters of overweight fathers. Down-stream analyses showed that the hypoxia signaling pathway which is regulated by miR-874, one of the miRNAs down-regulated in their mammary tissue, was active in normal mammary glands and tumors.

Conclusions: Using a mouse model, our study provides evidence that paternal overweight, around the time of conception, reprograms daughters’ mammary gland development, epigenetic profile and increase their mammary cancer risk. Studies are underway to determine whether the observed epigenetic changes are functionally responsible for increased breast cancer risk observed in the offspring of overweight males. If confirmed in humans, our findings could have important implications since it supports the notion that the familial or heritable aspect of breast cancer can be due not only to genetic factors but could also result from ancestral exposure and possibly inherited through modifiers of gene expression such as epigenetic mechanisms.

Citation Format: Camile Castilho Fontelles, Elissa Carney, Johan Clarke, Nguyen Nguyen, Chao Yin, Lu Jin, Leena Hilakivi-Clarke, Thomas Prates Ong, Zuolin Cheng, Yi Fu, Yue Wang, Sonia M. De Assis. Paternal overweight leads to reprogramming of daughters’ breast cancer risk in a mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-301.