Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming

Abstract

Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced breast cancer. However, the treatment process is often accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography–mass spectrometry. We observed significant changes in 25 metabolites, of which, 21 exhibited increased levels (>1.5-fold change and p < 0.05) and 4 exhibited decreased levels (<0.75-fold change and p < 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP). Furthermore, most of the enzymes involved in glycolysis, the HBP, and the TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways can serve as targets for the treatment of chemoresistance in breast cancer.

Recent advances in breast cancer cell line research

“…The researchers found that these changes were associated with alterations in the expression of genes involved in glucose, lipid, and amino acid metabolism. These findings suggest that metabolic reprogramming may be a key factor in the development of drug resistance and metastasis in breast cancer 20 …”

“…These findings suggest that metabolic reprogramming may be a key factor in the development of drug resistance and metastasis in breast cancer. 20 Gene expression-based profiling by Kay et al resulted in breast cancer cell line classification into four major subtypes: luminal A, luminal B, basal-like, and claudin-low. 21 A study of DNA methylation patterns revealed a distinct subtype of breast cancer called HER2-positive/low basal that is characterized by high levels of DNA methylation.…”

Inhibiting MEK1 R189 citrullination enhances the chemosensitivity of docetaxel to multiple tumour cells

“…Consistent with the results obtained from the in vitro cell culture, BB-Cla combined with Doc has an obviously additive inhibitory effect against the expression of CD133 and SOX2 in tumour tissues (figure 3 b and electronic supplementary material, S2 b ). Of note, the invasive ability of tumour cells is closely related to the characteristics of tumour stemness [51,52]. We continued to detect the changes of the cell invasive ability upon drug treatment.…”

A Metabolism-Related Gene Signature Predicts the Prognosis of Breast Cancer Patients: Combined Analysis of High-Throughput Sequencing and Gene Chip Data Sets

“…Metabolism reprogramming has also been recognized as a mechanism of breast cancer resistance. The metabolic profiles showed that there were 25 metabolites with significant changes, including 4 exhibited decreased levels and 21 exhibited increased levels, in doxorubicin-resistant MCF-7 cells [40]. Min et al reported that the level of G6PD (glucose-6-phosphate dehydrogenase) and metabolites of 3-phosphoglycerate and ribulose-5-phosphate production were both increased in paclitaxel-resistant cells [41].…”