Abstract 4826: Maternal high butter fat intake heightens mammary cancer risk in offsprings gestationally exposed to bisphenol A at environmentally relevant dose

In utero exposure to bisphenol A (BPA) at 250ug/kg BW was shown to augment mammary cancer risk in rodent models. High fat diet is widely believed to be a major risk of breast cancer (BCa). It is therefore important to investigate whether maternal high fat intake could potentially heighten mammary cancer risk associated to gestational BPA exposure. In this study, we exposed Sprague Dawley rats with different doses of BPA (2.5-2500ug/kg BW) mixed with high butter-based diet (HBF) in the period from preconception to birth. DMBA-PND50 protocol was followed. In the presence of HBF, we observed non-monotonic effects of BPA in cancer incidence as well as in the number of terminal end buds of PND21 mammary glands. Both results were peaked at a dosage of 25ug/kg BW BPA and the effects were significant when compared with HBF alone group. We further analyzed transcriptomic data of microdissected epithelia of PND21 mammary glands from BPA (25ug/kg BW) group as well as HBF group and revealed that two specific cancer networks involving ERK and androgen receptor signaling were dysregulated. DNA methylation is one of the key mechanisms to dysregulate and impair the transcription of two selected top genes, Car7 and Kcnv2, as supported by our bisulfite-sequencing data. These data suggest that in utero BPA exposure could epigenetically modify gene expression and predispose cancer risk during early development. More importantly, some BPA genes are of high human relevance because seven selected BPA genes could dichotomize patients into two groups with significant difference in overall survival in a TCGA cancer cohort. The prognostic power of the genes was further enhanced in the survival analysis of Caucasian with ER positive patients. In conclusion, our data strongly suggest that BPA predisposes higher cancer risk by dysregulating gene expression during early mammary gland development in the presence of HBF, which could facilitate cancer development later in life. Citation Format: Yuet-Kin Leung, Vinothini Govindarajah, Ana Cheong, Dan Song, Xuegong Zhu, Jun Ying, Ady Kendler, Mario Medvedovic, Scott Belcher, Shuk-Mei Ho. Maternal high butter fat intake heightens mammary cancer risk in offsprings gestationally exposed to bisphenol A at environmentally relevant dose [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 4826. doi:10.1158/1538-7445.AM2017-4826