Correlation between the Warburg effect and progression of triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is ineligible for hormonal therapy and Her-2-targeted therapy due to the negative expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Although targeted therapy and immunotherapy have been shown to attenuate the aggressiveness of TNBC partially, few patients have benefited from them. The conventional treatment for TNBC remains chemotherapy. Chemoresistance, however, impedes therapeutic progress over time, and chemotherapy toxicity increases the burden of cancer on patients. Therefore, introducing more advantageous TNBC treatment options is a necessity. Metabolic reprogramming centered on glucose metabolism is considered a hallmark of tumors. It is described as tumor cells tend to convert glucose to lactate even under normoxic conditions, a phenomenon known as the Warburg effect. Similar to Darwinian evolution, its emergence is attributed to the selective pressures formed by the hypoxic microenvironment of pre-malignant lesions. Of note, the Warburg effect does not disappear with changes in the microenvironment after the formation of malignant tumor phenotypes. Instead, it forms a constitutive expression mediated by mutations or epigenetic modifications, providing a robust selective survival advantage for primary and metastatic lesions. Expanding evidence has demonstrated that the Warburg effect mediates multiple invasive behaviors in TNBC, including proliferation, metastasis, recurrence, immune escape, and multidrug resistance. Moreover, the Warburg effect-targeted therapy has been testified to be feasible in inhibiting TNBC progression. However, not all TNBCs are sensitive to glycolysis inhibitors because TNBC cells flexibly switch their metabolic patterns to cope with different survival pressures, namely metabolic plasticity. Between the Warburg effect-targeted medicines and the actual curative effect, metabolic plasticity creates a divide that must be continuously researched and bridged.

Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway

“…The intricate interplay between metabolism and PI3K inhibitors in breast cancer underscores the nuanced nature of targeted therapy. Metabolically, breast cancer cells prominently exhibit the Warburg effect, marked by heightened glucose uptake and glycolysis to sustain rapid cellular proliferation [ 161 , 162 ]. Altered lipid metabolism and increased reliance on specific amino acids further accentuate the metabolic demands associated with abnormal growth.…”

The Molecular Mechanisms behind Advanced Breast Cancer Metabolism: Warburg Effect, OXPHOS, and Calcium

“…Some studies have shown mutations in mitochondrial enzymes or mitochondrial DNA as possible contributors to the Warburg effect, however, dysregulation of signaling pathways, activation of certain oncogenes, mutations in tumor suppressors and the tumor microenvironment (TME) appear to be the major contributors on the metabolic reprogramming of cancer [ 7 – 10 ]. As these intricate mechanisms continue to be explored, it is acknowledged that the observed metabolic phenotype differences vary not only across cancer types but by the degree of malignancy, with more aggressive and invasive cancers generally exhibiting elevated glycolytic fluxes [ 11 – 14 ]. This metabolic adaptation that favors glycolysis, leads to the production of various glucose byproducts linked to different metabolic pathways, such as the pentose phosphate pathway (PPP), and the synthesis of essential biomolecules including nucleotides, amino acids, and lipids.…”

“…Tumor cells that rely on glycolysis are capable of surviving in a consistent hypoxic environment. Hypoxia further induces matrix remodeling, influencing the metabolic profile of TNBC cells [ 14 ]. The extent to which breast cancer cells exhibit the Warburg effect and utilize OXPHOS can indeed vary significantly among distinct subtypes of breast cancer.…”

The Significance of Microenvironmental and Circulating Lactate in Breast Cancer

“…The metabolic switch toward aerobic glycolysis (known as the Warburg effect) is also a topical research field in breast cancer (BC) [15]. Triple-negative breast cancers (TNBCs, lacking the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER2)) can benefit from this metabolic switch and, consistently, can be targeted by novel therapeutic compounds called glycolysis inhibitors.…”