Abstract 644: Ancestral paternal obesity: Systemic versus local effects on offspring mammary tissue development and tumorigenesis

Background: Obesity and overweight are risk factors for breast cancer, particularly in the post-menopausal years. We recently reported that having a history of ancestral overweight from the paternal lineage is enough to increase breast cancer susceptibility in daughters. Using a mouse model, we demonstrated that paternal consumption of an obesity inducing diet (OID) altered mammary gland development, increased mammary carcinogenesis and disrupted metabolic parameters in the female offspring, compared to the female offspring of fathers who consumed only control (CO) diet. Given both the systemic and local the mammary tissue alterations observed, we aimed to investigate in more details why daughters of overweight fathers are at increased risk for breast cancer. More specifically, we used mammary gland transplantation experiments to study whether this ancestrally-induced breast cancer predisposition is linked to systemic factors and/or mammary tissue confined changes in daughters. Material and methods: Male mice were exposed either to a control (CO) or to high-fat (OID) diet. CO and OID male mice were then mated with female mice fed CO diet exclusively. Female offspring of both CO and OID male mice underwent a mammary gland transplantation surgery. Briefly, female offspring had their mammary fat pad area between the nipple and the proximal lymph node excised. Afterwards, mammary tissue fragments (1 mm3) of a donor mouse, either CO or OID female offspring, were implanted into a pocket made in the cleared fat pad. The transplantations were performed from CO female offspring donors to both CO [CO(CO)] and OID [OID(CO)] female offspring hosts, as well as from OID female offspring donors to both CO [CO(OID)] and OID [OID(OID)] female offspring hosts. Approximately 10 weeks post-surgery, the mammary glands were collected, photographed and analyzed using ImageJ software to determine branching density, epithelial elongation and number of Terminal End Buds. Cell proliferation was assessed by ki-67 and cell apoptosis was measured on ImageJ software. Results: Our preliminary data shows that CO(OID) had more (p≤0.05) articulated mammary branching morphogenesis than CO(CO). OID(CO) displayed marginal increase (p≤0.09) in the mammary gland area, as well as in the mammary ductal elongation, compared to CO(OID). Additionally, the number of apoptotic cells within mammary ducts and lobules is higher in CO(OID) compared to OID(CO). In contrast, the number of proliferating cells is higher in OID(CO) mammary gland compared to CO(OID). Conclusion: Altogether, our findings suggest that daughters of overweight fathers have both systemic and mammary gland confined factors alterations that ultimately lead to higher breast cancer risk in adulthood. However, further data is needed to corroborate this hypothesis. Our ongoing mammary tumor transplantation studies should provide further insight. Citation Format: Camile C. Fontelles, Anni Warri, Raquel S. Da Cruz, Maria I. Cruz, Ersilia Barin, Sonia De Assis. Ancestral paternal obesity: Systemic versus local effects on offspring mammary tissue development and tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 644.