The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy

Laura Bornes, Lennart J. Winden, Veerle C. M. Geurts, Beaunelle Bruijn, Leyla Azarang, Mirthe Lanfermeijer, Marika Caruso, Natalie Proost, Manon Boeije, Jeroen O. Lohuis, Guillaume Belthier, Eulàlia Noguera Delgado, Nadia Gruil, Judith R. Kroep, Marieke Ven, Renee Menezes, Jelle Wesseling, Marleen Kok, Sabine Linn, Annegien Broeks, Huub H. Rossum, Colinda L. G. J. Scheele () and Jacco Rheenen ()
Additional contact information
Laura Bornes: The Netherlands Cancer Institute
Lennart J. Winden: The Netherlands Cancer Institute
Veerle C. M. Geurts: The Netherlands Cancer Institute
Beaunelle Bruijn: KU Leuven Department of Oncology
Leyla Azarang: The Netherlands Cancer Institute
Mirthe Lanfermeijer: The Netherlands Cancer Institute
Marika Caruso: KU Leuven Department of Oncology
Natalie Proost: The Netherlands Cancer Institute
Manon Boeije: The Netherlands Cancer Institute
Jeroen O. Lohuis: The Netherlands Cancer Institute
Guillaume Belthier: The Netherlands Cancer Institute
Eulàlia Noguera Delgado: The Netherlands Cancer Institute
Nadia Gruil: Leiden University Medical Center
Judith R. Kroep: Leiden University Medical Center
Marieke Ven: The Netherlands Cancer Institute
Renee Menezes: The Netherlands Cancer Institute
Jelle Wesseling: The Netherlands Cancer Institute
Marleen Kok: The Netherlands Cancer Institute
Sabine Linn: The Netherlands Cancer Institute
Annegien Broeks: The Netherlands Cancer Institute
Huub H. Rossum: The Netherlands Cancer Institute
Colinda L. G. J. Scheele: KU Leuven Department of Oncology
Jacco Rheenen: The Netherlands Cancer Institute

Nature, 2025, vol. 637, issue 8044, 195-204

Abstract: Abstract The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype1. Here we identify the oestrous cycle as an important contributor to this heterogeneity. In three mouse models of breast cancer, we show reduced responses to NAC when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage. Similar findings were observed in retrospective premenopausal cohorts of human patients. Mechanistically, the dioestrus stage exhibits systemic and localized changes, including (1) an increased number of cells undergoing epithelial-to-mesenchymal transition linked to chemoresistance2–4 and (2) decreased tumour vessel diameter, suggesting potential constraints to drug sensitivity and delivery. In addition, an elevated presence of macrophages, previously associated with chemoresistance induction5, characterizes the dioestrus phase. Whereas NAC disrupts the oestrous cycle, this elevated macrophage prevalence persists and depletion of macrophages mitigates the reduced therapy response observed when initiating treatment during dioestrus. Our data collectively demonstrate the oestrous cycle as a crucial infradian rhythm determining chemosensitivity, warranting future clinical studies to exploit optimal treatment initiation timing for enhanced chemotherapy outcomes.

Date: 2025
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DOI: 10.1038/s41586-024-08276-1

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