Abstract 1257: Paternal sub-optimal nutrition leads to programming of daughters' breast cancer risk in a mouse model

Abstract

Abstract Background: Dietary patterns are known to induce epigenetic changes in paternal sperm. Acquired epigenetic traits have been shown to be transmitted from parents to offspring via the germ-line (eggs and sperm) and modulate disease risk in offspring. We have shown before that paternal overweight around the time of conception leads to reprogramming of the mammary gland tissue and breast cancer risk in the offspring. Here, we investigated whether paternal sub-optimal nutrition (low protein diet) could epigenetically reprogram the father's germ-line and alter daughters' likelihood of developing breast cancer, using a mouse model. Methods: Male mice were fed control (Con) or low-protein (LP) 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 on post-natal day (PND) 50, which was used for morphologic and molecular analyses. Another sub-set of female offspring was treated with 9,12-dimethylbenz[a]anthracene (DMBA) to induce mammary tumors. Results: We found that male LP consumption alters the non-coding RNA content and DNA methylation patterns of the sperm in agreement with previous findings. We also observed that, compared to Con offspring, the female offspring of LP fathers had lower birth weight (p=0.035). This decrease in body weight persisted through sexual maturity when females begun to gain more weight than their control counterparts (p>0.001). In addition, mammary glands of LP offspring were larger(p=0.02) and had increased epithelial density (p=0.001) when compared to Con on PND50. In addition, we found that LP mammary glands had epigenetic alterations, including in DNA methylation and the miRNA expression profiles. These changes in normal mammary tissue were associated with higher rates of DMBA-induced mammary tumor (p=0.04), increased tumor growth (p=0.03) and reduced tumor latency in LP offspring (p=0.03). Mammary tumors of LP offspring had lower rates of apoptosis, which may explain the increased tumor growth in this group. However, the mechanisms mediating this effect still needs to be elucidated. Conclusion: Paternal sub-optimal nutrition programs the female offspring mammary gland development and breast cancer risk. Whether this increase in cancer risk is due to local mammary tissue changes or whether systemic changes play a role remains to be investigated. It also remains to be determined whether epigenetic changes in paternal sperm are functionally linked to changes in mammary gland development and cancer risk. Citation Format: Raquel Santana, Elissa Carney, Hong Cao, Johan Clarke, M. Idalia Cruz, Lu Jin, Yi Fu, Zuolin Cheng, Joseph (Yue) Wang, Sonia de Assis. Paternal sub-optimal nutrition leads to programming of daughters' breast cancer risk in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1257. doi:10.1158/1538-7445.AM2017-1257