Metabolic reprogramming in breast cancer results in distinct mitochondrial bioenergetics between luminal and basal subtypes

Abstract

Mitochondrial dysfunction is a key feature of cancer and is frequently associated with increased aggressiveness and metastatic potential. Recent evidence has brought to light a metabolic rewiring that takes place during the epithelial‐to‐mesenchymal transition (EMT), a process that drives the invasive capability of malignant tumors, and highlights a mechanistic link between mitochondrial dysfunction and EMT that has been only partially investigated. In this study, we characterized mitochondrial function and bioenergetic status of cultured human breast cancer cell lines, including luminal‐like and basal‐like subtypes. Through a combination of biochemical and functional studies, we demonstrated that basal‐like cell lines exhibit impaired, but not completely inactive, mitochondrial function, and rely on a consequent metabolic switch to glycolysis to support their ATP demand. These altered metabolic activities are linked to modifications of key electron transport chain proteins and a significant increase in levels of reactive oxygen species compared to luminal cells. Furthermore, we observed that the stable knockdown of EMT markers caused functional changes in mitochondria that result in acquisition of a hybrid glycolysis/OXPHOS phenotype in cancer cells as a means to sustain their metabolic demand.

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

“…Our research team has been addressing this phenomenon, as discussed in our previous works [22,29]. We hypothesize that the increased presence of PRDX1, induced by the altered redox and bioenergetic homeostasis that characterize TNBC cells [41], stabilizes to some extent the redox homeostasis in breast cancer cells, decreases further spontaneous mutagenesis, and slows down its progression into more aggressive forms, and thus it correlates with a more favorable prognosis. However, at the same time, PRDX1 does protect the malignant cells from immediate death due to oxidative stress, and thus promotes the cancerous growth, which suggests that the inhibition of PRDX1 in breast cancer could be a potential therapeutic approach in this disease, especially when combined with prooxidant therapies, such as Asc/Men.…”

1H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages

“…During these years, the clear role of specific metabolic pathways in driving pro-tumorigenic events including tumor growth, chemoresistance and plasticity, is emerged [19][20][21][22][23][24]. An over-expression of metabolic genes regulating glycolysis, aminoacyl-tRNA biosynthesis, pyrimidine biosynthesis, purine biosynthesis and pentose phosphate pathway characterize tumor tissues compared to normal samples, thus highlighting the hypothesis of a specific metabolic signature at the tumor level [25].…”

Metabolic Constrains Rule Metastasis Progression

“…In addition to this, an in-vitro study on lung cancer cell lines showed that TGFβ-mediated EMT increases mitochondrial reactive oxygen species (ROS) production and induces mitochondrial membrane potential drop [157]. Moreover, in-vitro works with breast cancer models showed that basal cell lines display significantly reduced mitochondrial function when compared with luminal cell lines [158]. On the other hand, in-vivo models of breast cancer have provided significant evidence that downregulation of the mitochondrial protein TMEM126A leads to increased invasiveness and metastasis [159].…”