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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Breast cancer survival is stage-dependent, with advanced cases often treated with chemoradiation.
• Chemotherapy resistance is a major cause of treatment failure in advanced breast cancer.
• Metabolic reprogramming is increasingly recognized as a key mechanism driving cancer drug resistance.

Purpose of the Study:

• To investigate the role of metabolic reprogramming in the development of doxorubicin resistance in breast cancer cells.
• To identify specific metabolic pathways and enzymes associated with drug resistance in breast cancer.

Main Methods:

• Established a doxorubicin-resistant MCF-7 (MCF-7-D500) cell line through prolonged in vitro doxorubicin exposure.
• Analyzed metabolic profiles of parental and resistant cells using liquid chromatography-mass spectrometry (LC-MS).
• Quantified changes in metabolite levels and assessed the expression of key metabolic enzymes.

Main Results:

• MCF-7-D500 cells displayed increased multidrug resistance, stemness, and invasiveness compared to parental MCF-7 cells.
• LC-MS analysis revealed significant alterations in 25 metabolites, with 21 upregulated and 4 downregulated in resistant cells.
• Upregulation of enzymes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and the hexosamine biosynthesis pathway (HBP) was observed in resistant cells.

Conclusions:

• Metabolic reprogramming, particularly the activation of glycolysis, TCA cycle, and HBP, is implicated in doxorubicin resistance in breast cancer.
• These altered metabolic pathways and their associated enzymes represent potential therapeutic targets for overcoming chemoresistance in breast cancer patients.
• Findings provide novel insights into the molecular mechanisms underlying drug resistance in breast cancer.