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

Mol Med. 2022 Feb 5;28(1):15. doi: 10.1186/s10020-022-00440-5.


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.

Keywords: Asymmetry; Breast cancer; Laterality; Left; Right.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Computational Biology
  • DNA Methylation
  • Electric Impedance*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Transcriptome
  • Tumor Microenvironment
  • Unilateral Breast Neoplasms / genetics*
  • Unilateral Breast Neoplasms / pathology*