Paternal overweight is associated with increased breast cancer risk in daughters in a mouse model

Abstract

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.

Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring

“…Thus, we studied the mammary cancer risk in control and LP daughters using a well-established [5, 27] carcinogen-induced mouse model of breast cancer. Tumor latency was significantly shorter in LP daughters compared with controls ( P  = 0.029; Fig.…”

“…However, paternal factors also play a role in the offspring’s birthweight [14]. In line with this, we recently reported that paternal high-fat diet intake or overweight leads to increased birthweight, alterations in mammary gland development, and higher rates of breast cancer risk in daughters in two rodent models [5, 6]. While no studies in humans have directly investigated the link between paternal nutrition and breast cancer in daughters, an association between other paternal factors and cancer risk in the progeny has been reported [15–17].…”

“…This established model of breast cancer has been used by us and others [5, 27]. Mice were examined for mammary tumors by palpation once per week, starting at week 2 after the last dose of DMBA and continue for a total of 20 weeks.…”

Paternal obesity and epigenetic inheritance of breast cancer: The role of systemic effects and transmission to the second generation

“…We previously reported that paternal consumption of obesity-inducing diets (OID) at the pre-243 conception window increased female offspring's susceptibility to breast cancer [15,16]. In those 244 studies, we also described mammary gland morphological changes as well as metabolic 245 dysfunction-a phenotype also reported by others-in offspring of obese fathers [16,18,19,32].…”

“…However, a role for paternal exposures in 67 modulating breast cancer predisposition in offspring has emerged in recent years. We recently 68 showed that paternal obesity, malnutrition and consumption of a high-fat diet all lead to 69 increased breast cancer development in offspring [15][16][17], a phenotype associated with changes 70 in normal mammary gland development. We also found that a recurrent phenotype 71 accompanying offspring's cancer predisposition is metabolic dysfunction [16][17][18], raising the 72 possibility that paternally-induced cancer development could be a function of both systemic 73 effects as well as tissue specific changes.…”