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

MASUELLI, SOFIA; REAL, SEBASTIÁN; CAMPOY, EMANUEL MARTIN; BRANHAM, MARIA TERESITA; MARZESE, DIEGO MATÍAS; MATTHEW, SALOMON; DE BLAS, GERARDO; MICHAEL, LEVIN; MARIA, ROQUÉ

Mar del Plata, Buenos Aires

Congreso; LXVII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2022

Sociedad Argentina de Investigación Clínica

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, geneexpression, and DNA methylation. We postulate that a differentialL/R tumor-microenvironment crosstalk generates different tumorigenesismechanisms. Methods: We performed in-silico analyses on human breast tumors of public datasets, developed xenografted L/Rtumors in mice, and conditioned MDA-MB-231 cultured cells withL/R human mammary extracts. Results: We found L/R differentialDNA methylation involved in embryogenic and neuron-like functions(Gene Enrichment Analyses, adjusted p values < 0.05). Focusing onion-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 presentedincreased methylation of hyperpolarizing ion channel genesand increased Ca2+ concentration (unpaired T-test with Welch’s correction,p < 0.003; Kruskal–Wallis test, p < 0.0001) and depolarizedmembrane potential (L/R-fluorescence ratio, One-sample T-test withhypothetical R value = 1, p = 0.04), compared to R-ones. Functionallaterality consequences were associated with increased proliferationin left tumors, assessed by KI67 expression (Unpaired T-test, p =0.002) and mitotic count (Unpaired T-test, p > 0.5). Conclusions: Ourfindings reveal considerable L/R asymmetry in cancer processes,and suggest specific L/R epigenetic and bioelectric differences asfuture targets for cancer therapeutic approaches in the breast andmany other paired organs.