Breast Cancer Subtypes Present a Differential Production of Reactive Oxygen Species (ROS) and Susceptibility to Antioxidant Treatment

Abstract

Due to their crucial role in cell metabolism and homeostasis, alterations in mitochondrial biology and function have been related to the progression of diverse diseases including cancer. One of the consequences associated to mitochondrial dysfunction is the production of reactive oxygen species (ROS). ROS are known to have a controversial role during cancer initiation and progression and although several studies have tried to manipulate intracellular ROS levels using antioxidants or pro-oxidation conditions, it is not yet clear how to target oxidation for cancer therapy. In this study, we found differences in mitochondrial morphology in breast cancer cells when compared to a non-tumorigenic cell line and differences in mitochondrial function among breast cancer subtypes when exploring gene-expression data from the TCGA tumor dataset. Interestingly, we found increased ROS levels in triple negative breast cancer (TNBC) cell lines and a dependency on ROS for survival since antioxidant treatment induced cell death in TNBC cells but not in an estrogen receptor positive (ER+) cell line. Moreover, we identified the mitochondria as the main source of ROS in TNBC cell lines. Our results indicate a potential use for ROS as a target for therapy in the TNBC subtype which currently has the worst prognosis among all breast cancers and remains as the only breast cancer subtype which lacks a targeted therapy.

Mitochondrial DNA Mutation Analysis in Breast Cancer: Shifting From Germline Heteroplasmy Toward Homoplasmy in Tumors

“…We suggest that the elevated mutational burden of hormonereceptor-positive tumors (LA and LB) could be explained by superoxide radical formation during estrogen metabolism, which promotes mtDNA alterations (103,109). A recent study revealed a differential expression profile of mitochondria-related genes among molecular subtypes of breast cancer, perhaps derived from the partial contribution of the mtDNA mutations in breast tumor biology (110). Increasing sample size and balancing tumor subtypes could support our observations.…”

Miro, a Rho GTPase genetically interacts with Alzheimer's disease-associated genes (Tau, Aβ42andAppl) inDrosophila melanogaster

“…MitoSOX is a DHE derivative that possesses a cationic triphenylphosphonium group (TPP+), which helps in the transport to the mitochondrial matrix (Fuentes-Retamal et al, 2020;Roelofs et al, 2015). In the presence of ROS, MitoSOX gets oxidized and emits red fluorescence which was used to measure the ROS production (Forkink et al, 2010;Sarmiento-Salinas et al, 2019). For this, third instar larval brains from desired genotypes were dissected in cold Hanks' Balanced Salt Solution (HBSS) and incubated in 5 µM MitoSOX Red and 1 µM MitoTracker Green FM (cat.…”

Disruption of Redox Balance Enhances the Effects of BRAF-inhibition in Melanoma Cells

“…In summary, our findings suggest that modulation of cancer antioxidant defense could be exploited to augment the benefits of existing therapies in melanoma (Khamari et al, 2018;Yuan et al, 2018) . This strategy may extend beyond melanoma, as antioxidant pathways have been implicated in tumor progression, and drug resistance (Harris et al, 2015;Ji et al, 2018;Sarmiento-Salinas et al, 2019) .…”

“…NADPH is produced via the Pentose Phosphate Pathway (PPP), and acts as a shared substrate for both GSH regeneration, and ROS production, thus maintaining an optimum redox balance within cancer cells. Even within cancer subtypes, this redox state could be heterogeneous (Sarmiento-Salinas et al, 2019) , motivating further research to examine how this balance could be altered for therapeutic benefits.…”