When left does not seem right: epigenetic and bioelectric differences between left- and right-sided breast cancer

Rodolfo Arias,Sofía Masuelli,María Teresita Branham,Diego Matías Marzese,Sebastián Real,Matthew Salomon,Emanuel Campoy,Michael Levin,María Roqué,Gerardo De Blas

doi:10.1186/s10020-022-00440-5

Abstract

BackgroundDuring 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.MethodsWe performed in-silico analyses on breast tumors of public datasets, developed xenografted tumors, and conditioned MDA-MB-231 cells with L/R mammary extracts.ResultsWe 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.ConclusionsOur 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.

Highlights

During embryogenesis lateral symmetry is broken, giving rise to Left/Right (L/R) breast tissues with distinct identity
We calculated the L/R DNA methylation mean for each genomic region and ranked their absolute differences
DNA methylation differences In‐silico L/R DNA methylation differences in breast tumors The methylation profile of ~ 16,000 genomic regions were analyzed in 782 primary breast carcinomas (394 L and 388 R)

Summary

Introduction

During embryogenesis lateral symmetry is broken, giving rise to Left/Right (L/R) breast tissues with distinct identity. We postulate that a differential L/R tumor-microenvironment crosstalk generates different tumorigenesis mechanisms. Some organs, such as the heart or viscera are asymmetric: their structures to the left and right of the body midplane are consistently different in all normal individuals (Monsoro-Burq and Levin 2018). It can be said that the microenvironment contributes to the decision-making strategy of a tumor to reach the cancer hallmarks (Hanahan and Weinberg 2011) In this context, epigenetics and bioelectricity have a crucial role since both constitute vehicles by which external signals reach and modulate the transcriptome in an experience-dependent and dynamic way

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