The Yin and Yang of Breast Cancer: Ion Channels as Determinants of Left-Right Functional Differences.

Breast cancer is a complex and heterogeneous disease that displays diverse molecular subtypes and clinical outcomes. Although it is known that the location of tumors can affect their biological behavior, the underlying mechanisms are not fully understood. In our previous study, we found a differential methylation profile and membrane potential 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 features. To achieve this, experiments were conducted in mammary tumors in mice, human patient samples, and with data from public datasets. The results revealed that L-sided tumors have a more depolarized state than R-sided. We identified 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-tumors. Additionally, in silico analyses show that the signature correlates inversely with DNA methylation writers and with key biological processes involved in cancer progression, such as proliferation and stemness. The signature also correlates inversely with patient survival rates. In an in vivo mouse model, we confirmed that KI67 and CD44 markers were increased in L-sided tumors and a similar tendency for KI67 was found in patient L-tumors. Overall, this study provides new insights into the potential impact of anatomical location on breast cancer biology and highlights the need for further investigation into possible differential treatment options.

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

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.

A modelling study highlights the power of detecting and isolating asymptomatic or very mildly affected individuals for COVID-19 epidemic management.

BACKGROUND: Mathematical modelling of infectious diseases is a powerful tool for the design of management policies and a fundamental part of the arsenal currently deployed to deal with the COVID-19 pandemic. METHODS: We present a compartmental model for the disease where symptomatic and asymptomatic individuals move separately. We introduced healthcare burden parameters allowing to infer possible containment and suppression strategies. In addition, the model was scaled up to describe different interconnected areas, giving the possibility to trigger regionalized measures. It was specially adjusted to Mendoza-Argentina's parameters, but is easily adaptable for elsewhere. RESULTS: Overall, the simulations we carried out were notably more effective when mitigation measures were not relaxed in between the suppressive actions. Since asymptomatics or very mildly affected patients are the vast majority, we studied the impact of detecting and isolating them. The removal of asymptomatics from the infectious pool remarkably lowered the effective reproduction number, healthcare burden and overall fatality. Furthermore, different suppression triggers regarding ICU occupancy were attempted. The best scenario was found to be the combination of ICU occupancy triggers (on: 50%, off: 30%) with the detection and isolation of asymptomatic individuals. In the ideal assumption that 45% of the asymptomatics could be detected and isolated, there would be no need for complete lockdown, and Mendoza's healthcare system would not collapse. CONCLUSIONS: Our model and its analysis inform that the detection and isolation of all infected individuals, without leaving aside the asymptomatic group is the key to surpass this pandemic.