Metabolic Switch in Endocrine Resistant Estrogen Receptor Positive Breast Cancer

Area of Science:

• Oncology
• Metabolic pathways
• Breast cancer research

Background:

• Endocrine resistance is a major obstacle in treating estrogen receptor-positive (ER+) breast cancer.
• Metabolic reprogramming is a key driver of endocrine resistance, presenting a potential therapeutic target.
• Understanding conserved metabolic changes and their impact on ER DNA binding is crucial for effective treatment strategies.

Purpose of the Study:

• To investigate the role of metabolic reprogramming in endocrine resistance in ER+ breast cancer.
• To evaluate dimethyl fumarate (DMF) as a potential agent to restore sensitivity to tamoxifen (Tam) and fulvestrant (Fulv).
• To elucidate how metabolic alterations influence estrogen receptor (ER) DNA-binding patterns in resistant cells.

Main Methods:

• Generated tamoxifen-resistant (TamR) and fulvestrant-resistant (FulvR) cell lines from six ER+ breast cancer cell lines.
• Performed metabolomic profiling, RNA sequencing, proteomics, and CUT&RUN assays to characterize metabolic and molecular changes.
• Assessed DMF's efficacy in reversing resistance, restoring tricarboxylic acid (TCA) cycle function, and re-establishing ER DNA-binding patterns.

Main Results:

• Resistant cells showed disrupted TCA cycle activity, reduced glutathione, and altered nucleotide/amino acid metabolism.
• DMF treatment restored TCA cycle intermediates, reversed resistance in TamR and FulvR cells, and modulated mevalonate pathway enzymes.
• DMF restored ER DNA-binding patterns in TamR cells, re-sensitizing them to tamoxifen, but modulated ER-cofactor interactions in FulvR cells without restoring parental binding signatures.

Conclusions:

• Metabolic reprogramming significantly impacts ER DNA-binding activity and resistance mechanisms in ER+ breast cancer.
• Targeting metabolic vulnerabilities, such as TCA cycle disruptions with agents like DMF, can reprogram ER signaling and overcome resistance.
• This study provides valuable multi-omics data on metabolic adaptation in endocrine-resistant breast cancer, enhancing understanding of ER function alterations.