THE LATERALITY OF BREAST CANCER: ION CHANNELS AS DETERMINANTS OF LEFT–RIGHT FUNCTIONAL DIFFERENCES

MASUELLI, SOFÍA; REAL SEBASTIAN; MCMILLEN, PATRICK; OUDIN, MADELEINE; LEVIN, MICHAEL; ROQUÉ MARÍA

Mar del Plata

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2023

Breast cancer is a heterogeneous disease that displays diverse mo- lecular subtypes and clinical outcomes. Although it is known that the location of tumors can affect biological behavior, the underly- ing mechanisms are not fully understood. In our previous study, we found a differential methylation profile and membrane potential state between left (L) and right (R) sided breast tumors. In this current study, we aimed to identify the ion channels responsible for this phenomenon and determine any associated phenotypic feature. To achieve this, experiments were conducted in mammary tumors in mice, human patient samples, and with data from public datasets. Results from the mouse model revealed that L-sided tumors have a more depolarized state than R-sided (unpaired t-test, p=0.01). We identified in-silico a 6-ion-channel-gene signature (CACNA1C, CACNA2D2, CACNB2, KCNJ11, SCN3A, and SCN3B) associated with the side: L-tumors exhibit lower expression levels than R-tu- mors (Mann–Whitney test, p=0.005). Additionally, the signature cor- relates inversely with DNA methylation writers (r= -0.42, Spearman correlation test, p < 0.0001) and with key biological processes in- volved in cancer progression, such as proliferation and stemness scores (r=-0.47 and r =-0.62 respectively, Spearman correlation test, p< 0.0001) (ROC curve analyses for proliferation and stemness re- spectively: AUC=0.74, SE=0.02, 95% CI=0.698 to 0.782, p