Metabolic Switch in Endocrine Resistant Estrogen Receptor Positive Breast Cancer

PURPOSE: The development of endocrine resistance remains a significant challenge in the clinical management of estrogen receptor-positive (ER+) breast cancer.

Metabolic reprogramming is a prominent component of endocrine resistance and a potential therapeutic intervention point.

However, a limited understanding of which metabolic changes are conserved across the heterogeneous landscape of ER+ breast cancer or how metabolic changes factor into ER DNA binding patterns hinder our ability to target metabolic adaptation as a treatment strategy.

This study uses dimethyl fumarate (DMF) to restore tamoxifen (Tam) and fulvestrant (Fulv) sensitivity in endocrine-resistant cell lines and investigates how metabolic changes influence ER DNA-binding patterns.

EXPERIMENTAL DESIGN: To address the challenge of metabolic adaptation in anti-endocrine resistance, we generated Tam and Fulv resistance in six ER+ breast cancer (BC) cell lines, representing ductal (MCF7, T47D, ZR75–1, and UCD12), lobular (MDA-MB-134--VI), and HER2 amplified (BT474) BC molecular phenotypes.

Metabolomic profiling, RNA sequencing, proteomics, and CUT&RUN assays were completed to characterize metabolic shifts, transcriptional and protein changes, and ER DNA-binding patterns in resistant cells.

Dimethyl fumarate was assessed for its ability to reverse Tam and Fulv resistance, restore tricarboxylic acid cycle (TCA) cycle function, and restore parental cell (endocrine sensitive) ER DNA binding patterns.

RESULTS: Tamoxifen-resistant (TamR) and fulvestrant-resistant (FulvR) cells exhibited disrupted TCA cycle activity, reduced glutathione levels, and altered nucleotide and amino acid metabolism.

DMF treatment replenished TCA cycle intermediates and reversed resistance in both TamR and FulvR cells.

DMF also increased mevalonate pathway enzyme expression in both TamR and FulvR cells, with TamR cells upregulating enzymes in the cholesterol synthesis phase and FulvR enhancing enzymes in the early part of the pathway.

DMF restored ER DNA-binding patterns in TamR cells to resemble parental cells, re-sensitizing them to Tam.

In FulvR cells, DMF reversed resistance by modulating ER-cofactor interactions but did not restore parental ER DNA-binding signatures.

CONCLUSIONS: Our findings provide new insights into how metabolic reprogramming affects ER DNA-binding activity in endocrine-resistant breast cancer.

We demonstrate how altering metabolism can reprogram ER signaling and influence resistance mechanisms by targeting metabolic vulnerabilities, such as TCA cycle disruptions.

Additionally, our data provide a comprehensive metabolomic, RNA-seq, and CUT&RUN data set relevant to tumor metabolic adaptation leading to acquired endocrine resistance in highly utilized ER+ breast cancer cell lines.

This study improves our understanding of how metabolic states alter ER function in endocrine-resistant breast cancer.