Epigenetics, bioelectricity and laterality of breast cancer

Sofia Masuelli¹, Sebastián Real¹, Emanuel Campoy¹, Diego Marzese², Matt Salomon³, Gerardo De Blas¹, Rodolfo Arias¹, María Roqué¹


In previous studies we found unexpectedly in patients that left-right (L-R) breast cancers (BC) differed in their methylation profiles (DM). We opened a new research line in which we hypothesize that, given the L-R environments of breast glands are non-identical: i. the bioelectric communication of the tumor with the L-R context differs, and ii. epigenetics has a crucial role in these differences. Our results, so far, are promising. We found in-silico that the top genes with L-R DM were involved in development, embryogenesis, and neural differentiation. We confirmed the same processes, by developing a MDA-MB231-Nod Scid Gama xenograft model and compared L-R tumoral methylation patterns by RRBS. With focus on ion channels, we found that depolarizing channels were more methylated in R breast tumors. This suggested that R sided tumors had a more polarized state as compared to L tumors. We setup an in-vitro model to treat MDA-MB231 cells with L-R conditioned extracts from normal human mammary glands and measured Ca2+ and Δψp with fluorescent probes. Cytometry assays confirmed bioelectric differences in the same direction: a more polarized state of right-treated cells. When deepening on epigenetic regulators, we found in-vitro a subtle increase of DNMT3 (de-novo methyltransferase) in left-treated cells, and confirmed it in-silico. Our studies support a non-explored epigenetic-bioelectric-laterality hypothesis for BC, which could serve as proof-of-principle for other bilateral tumors.