WHEN LEFT DOES NOT SEEM RIGHT: EPIGENETIC AND BIOELECTRIC DIFFERENCES BETWEEN LEFT AND RIGHT-SIDED BREAST CANCER

MASUELLI S; REAL, SEBASTIAN; CAMPOY E; BRANHAM MT; MARZESE, DIEGO M; SALOMON M; DE BLAS, GERARDO; MICHAEL, LEVIN; ROQUE MORENO MARIA

Congreso; REUNION SAIC 2022; 2022

Background: During embryogenesis lateral symmetry is broken, giving rise to Left/Right (L/R) breast tissues with distinct identity. L/R-sided breast tumors exhibit consistently-biased incidence, gene expression, and DNA methylation. We postulate that a differential L/R tumor-microenvironment crosstalk generates different tumorigenesis mechanisms.Methods: We performed in-silico analyses on human breast tumors of public datasets, developed xenografted L/R tumors in mice, and conditioned MDA-MB-231 cultured cells with L/R human mammary extracts.Results: We found L/R differential DNA methylation involved in embryogenic and neuron-like functions (Gene Enrichment Analyses, adjusted p values < 0.05). Focusing on ion-channels, we discovered significant L/R epigenetic differences (53.8% vs 66.6%, OR 0.5, 95%CI 0.11–2.13 in the in-vivo experiment; 49.01% vs 50%, OR 0.96, 95%CI 0.35–2.59 in the in-silico experiment) and bioelectric differences. Specifically, L-sided cells presented increased methylation of hyperpolarizing ion channel genes and increased Ca2+ concentration (unpaired T-test with Welch’s correction, p < 0.003; Kruskal–Wallis test, p < 0.0001) and depolarized membrane potential (L/R-fluorescence ratio, One-sample T-test with hypothetical R value = 1, p = 0.04), compared to R-ones. Functional laterality consequences were associated with increased proliferation in left tumors, assessed by KI67 expression (Unpaired T-test, p = 0.002) and mitotic count (Unpaired T-test, p > 0.5).Conclusions: Our findings reveal considerable L/R asymmetry in cancer processes, and suggest specific L/R epigenetic and bioelectric differences as future targets for cancer therapeutic approaches in the breast and many other paired organs.