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

MASUELLI S; REAL S; MCMILLEN; MICHAEL, LEVIN; OUDIN MADELEINE; ROQUÉ M

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI

Lugar: Basel; Año: 2023

1422-0067

Abstract: Breast cancer is a complex and heterogeneous disease that displays diverse molecularsubtypes and clinical outcomes. Although it is known that the location of tumors can affect theirbiological 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 forthis phenomenon and determine any associated phenotypic features. To achieve this, experimentswere conducted in mammary tumors in mice, human patient samples, and with data from publicdatasets. 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 methylationwriters and with key biological processes involved in cancer progression, such as proliferation andstemness. The signature also correlates inversely with patient survival rates. In an in vivo mousemodel, we confirmed that KI67 and CD44 markers were increased in L-sided tumors and a similartendency for KI67 was found in patient L-tumors. Overall, this study provides new insights into thepotential impact of anatomical location on breast cancer biology and highlights the need for furtherinvestigation into possible differential treatment options.