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

Molecular Medicine

Levin Michael¹  Diego Matías Marzese²  Salomon Matthew³  Arias Rodolfo⁴  Roqué María⁵  María Teresita Branham⁶  Campoy Emanuel⁷  Real Sebastián⁷  Gerardo De Blas⁷  Masuelli Sofía⁷ 

[1]Allen Discovery Center at Tufts University, 02115, Medford, MA, USA

[2]Cancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain

[3]Department of Medicine, Keck School of Medicine, University of Southern California, 90007, Los Angeles, CA, USA

[4]National Council of Scientific and Technological Research (IHEM-CONICET), PC:5500, Mendoza, Argentina

[5]National Council of Scientific and Technological Research (IHEM-CONICET), PC:5500, Mendoza, Argentina

[6]Exact Science Faculty, National University of Cuyo, PC:5500, Mendoza, Argentina

[7]National Council of Scientific and Technological Research (IHEM-CONICET), PC:5500, Mendoza, Argentina

[8]Medical School, Mendoza University, PC:5500, Mendoza, Argentina

[9]National Council of Scientific and Technological Research (IHEM-CONICET), PC:5500, Mendoza, Argentina

[10]Medical School, National University of Cuyo, PC:5500, Mendoza, Argentina

关键词: Asymmetry;    Laterality;    Left;    Right;    Breast cancer;   

DOI  :  10.1186/s10020-022-00440-5

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY