Abstract 1401: Deterring breast cancer progression. The critical role of a lipid-sphingolipid epigenetic mechanism of cell fate

Abstract Genetic and environmental factors cooperate to assure precise genome-wide epigenetic regulation of the mammary epithelia cell transcriptome. Our interest in regulatory epigenetic mechanisms that, by determining mammary epithelial cell decisions, are pivotal to deter the onset and progression of breast cancer, let us identify a regulatory epigenetic mechanism of mammary morphogenesis that links a physiological regulatory lipid of environmental origin (all-trans retinoic acid, RA) with sphingolipids capable of determining either cell death (ceramide, CER) or cell life (sphingosine 1 phosphate, S1P). Whenever RA, for different reasons, fails to perform the epigenetic transcriptional control of neutral sphingomyelinase 2 (nSMase2/SMDP3), involved in the synthesis of pro-apoptotic CER, S1P fosters both pro-proliferative and pro-invasive activity. Apparently, in the absence of epigenetic control of CER production by RA, S1P contributes to determine RA tumorigenic action. This study provides the rationale for combination therapeutic approaches with epigenetic drugs and inhibitors of either sphingosine kinase, the enzyme involved in S1P synthesis, or S1P receptors. This study was supported by the NCI R01 CA127614 grant (NS). Citation Format: Stefano Rossetti, Vincenzo Gagliostro, Nicoletta Sacchi. Deterring breast cancer progression. The critical role of a lipid-sphingolipid epigenetic mechanism of cell fate [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 1401. doi:10.1158/1538-7445.AM2017-1401