2. Academic Validation
  3. Fasting boosts breast cancer therapy efficacy via glucocorticoid activation

Fasting boosts breast cancer therapy efficacy via glucocorticoid activation

  • Nature. 2025 Dec 10. doi: 10.1038/s41586-025-09869-0.
Nuno Padrão 1 2,  Tesa M Severson 1 2,  Sebastian Gregoricchio 1 2,  Ana Guijarro 3,  Catrin Lutz 2 4,  Daniel Taranto 2 5,  Stefan Hutten 2 4,  Francesca Ligorio 6 7,  Angelica Persia 3 8,  Merel Roest 1 2,  Joyce Sanders 9,  Ji-Ying Song 10,  Sara Pires-Oliveira 9,  Maria Donaldson Collier 1 2,  Hugo Horlings 9,  Livia Pisciotta 3 8,  Filippo de Braud 6 11,  Claudio Vernieri 7 11,  Leila Akkari 2 5,  Jos Jonkers 2 4,  Alessio Nencioni 3 8,  Irene Caffa 12 13,  Wilbert Zwart 14 15 16
Affiliations

Affiliations

  • 1 Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 2 Oncode Institute, Utrecht, The Netherlands.
  • 3 Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
  • 4 Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 5 Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 6 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
  • 7 IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.
  • 8 IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  • 9 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 10 Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 11 University of Milan, Milan, Italy.
  • 12 Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy. [email protected].
  • 13 IRCCS Ospedale Policlinico San Martino, Genoa, Italy. [email protected].
  • 14 Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands. [email protected].
  • 15 Oncode Institute, Utrecht, The Netherlands. [email protected].
  • 16 Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands. [email protected].
PMID: 41372410 DOI: 10.1038/s41586-025-09869-0
Abstract

The majority of breast cancers are driven by oestrogen receptor-α (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients1. However, resistance is common and tumours often progress after years of endocrine suppression2. Periodic fasting enhances the efficacy of standard endocrine therapy and delays acquired drug resistance, although the underlying mechanisms remain unclear3. Here we show that fasting induces extensive epigenetic reprogramming in ERα-positive breast Cancer xenografts when combined with endocrine therapy, with large-scale activation of Glucocorticoid Receptor (GR) and Progesterone Receptor signalling and concomitant reduction in the activity of activator protein-1 (AP-1) family members. GR-driven gene programmes are selectively activated in in vivo models of ERα-positive breast Cancer during fasting, and GR knockout hinders the anti-tumour effects of fasting combined with tamoxifen. Exogenous administration of GR ligands recapitulates fasting-enhanced anti-oestrogen action, thus promoting tumour regression. Patients undergoing a cyclic fasting-mimicking diet exhibited increased blood progesterone and cortisol concentrations. Additionally, tumours collected after the fasting-mimicking diet showed an inverse correlation of GR activation with proliferation markers, providing clinical confirmation of our observations in animal models. Our results indicate that GR activation has a pivotal role in the ability of fasting to enhance endocrine therapy activity in breast Cancer and suggest that corticosteroid administration should be evaluated as an Adjuvant to endocrine therapy in this setting.

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