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Publications

Journal Article Epublish

PubMed: 42729982 DOI: 10.20517/cdr.2026.57

Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.

Cancer Drug Resist 9:30

Authors: Melis Poyraz, Buse Sari, Jérôme Ambroise, Melanie Spears, Martin Michaelis, Jindrich Cinatl, Romain Boidot, Kristian Serafimov, Olivier Feron, François P Duhoux, Manon Desgres, Cyril Corbet

Affiliations

  • Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels 1200, Belgium.
  • Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels 1200, Belgium.
  • Diagnostic Development, Ontario Institute for Cancer Research, Toronto M5G 1M1, Canada.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 3K9, Canada.
  • School of Natural Sciences, Stacey Building, University of Kent, Canterbury CT2 7NJ, UK.
  • Dr Petra Joh-Research Institute, Frankfurt am Main 60528, Germany.
  • Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Unit of Molecular Biology, Department of Biology and Pathology of Tumors, ICMUB UMR CNRS 6302, Dijon 21000, France.
  • IREC Metabolomics Core, UCLouvain, Brussels 1200, Belgium.
  • WEL Research Institute, Wavre 1300, Belgium.
  • Pole of Molecular Imaging, Radiotherapy and Oncology (MIRO), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels 1200, Belgium.
  • Institut Roi Albert II, Department of Medical Oncology, Cliniques universitaires Saint-Luc, Brussels 1200, Belgium.
  • Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels 1200, Belgium. These authors equally supervised the work.
  • Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Brussels 1200, Belgium. WEL Research Institute, Wavre 1300, Belgium. These authors equally supervised the work.

Abstract

Aim: Resistance to neoadjuvant chemotherapy remains a major challenge in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). Although anthracyclines and taxanes constitute the standard sequential regimen, the metabolic adaptations accompanying resistance to these agents remain poorly defined. We investigated whether chemoresistance is associated with shared or drug-specific metabolic alterations. Methods: Parental MCF-7 and ZR-75-1 cells and their anthracycline-, and taxane-resistant derivatives, were characterized through multi-omics, Seahorse-based metabolic flux, and pharmacological inhibition analyses, alongside validation in patient transcriptomic datasets. Results: Chemoresistant cells displayed reduced drug sensitivity and improved recovery following treatment withdrawal. Transcriptomic profiling revealed extensive yet largely distinct gene expression changes among resistant models, whereas metabolomics showed limited divergence. Functional studies demonstrated concurrent reductions in mitochondrial respiration and glycolytic capacity, indicating a low-bioenergetic phenotype without compensatory metabolic rewiring. Lipidomic changes were heterogeneous and model-dependent. Despite this overall metabolic constraint, spermidine and spermine levels were increased across all resistant models, whereas upregulation of the polyamine-related genes ATP13A4 and SAT1 was specific to anthracycline-resistant cells. Chemoresistant phenotypes conferred reduced sensitivity to mitochondrial inhibitors. In contrast, sensitivity to polyamine pathway inhibition varied across models. Clinical datasets corroborated key experimental features, showing increased ATP binding cassette subfamily B member 1 (ABCB1) expression and significant post-treatment suppression of oxidative phosphorylation and glycolysis signatures. Polyamine pathway enrichment trends were less uniform, reflecting clinical heterogeneity. Conclusion: Chemoresistance in HR+/HER2- BC is characterized by heterogeneous transcriptional remodeling but relative metabolic constraint. Clinical dataset validation confirms post-chemotherapy bioenergetic suppression, while polyamine alterations represent context-dependent adaptations rather than universal vulnerabilities.

MeSH

Cells, Genes, Breast Neoplasms, Pharmaceutical Preparations, Neoplasms, Phenotype, Drug Therapy, Polyamines, Breast, Anthracyclines, Therapeutics, Chemotherapy