When Left Does Not Seem Right: Epigenetic and Bioelectric Differences Between Left- and Right-Sided Breast Cancer

Abstract

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 breast tumors of public datasets, developed xenografted tumors, and conditioned MDA-MB-231 cells with L/R mammary extracts. Results: We found L/R differential DNA methylation involved in embryogenic and neuron-like functions. Focusing on ion-channels, we discovered significant L/R epigenetic and bioelectric differences. Specifically, L-sided cells presented increased methylation of hyperpolarizing ion channel genes and increased Ca2+ concentration and depolarized membrane potential, compared to R-ones. Functional consequences were associated with increased proliferation in left tumors, assessed by KI67 expression and mitotic count. 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.