The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy

• Published in: Nature (London) 2025-01, Vol.637 (8044), p.195-204
• Main Authors: Bornes, Laura, van Winden, Lennart J., Geurts, Veerle C. M., de Bruijn, Beaunelle, Azarang, Leyla, Lanfermeijer, Mirthe, Caruso, Marika, Proost, Natalie, Boeije, Manon, Lohuis, Jeroen O., Belthier, Guillaume, Noguera Delgado, Eulàlia, de Gruil, Nadia, Kroep, Judith R., van de Ven, Marieke, Menezes, Renee, Wesseling, Jelle, Kok, Marleen, Linn, Sabine, Broeks, Annegien, van Rossum, Huub H., Scheele, Colinda L. G. J., van Rheenen, Jacco
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 14/63; 14/69; 631/67/1059/99; 631/67/1347; 631/67/2329; 64/110; 64/60; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm - drug effects; Epithelial-Mesenchymal Transition - drug effects; Estrous Cycle - drug effects; Female; Humanities and Social Sciences; Humans; Macrophages - drug effects; Macrophages - metabolism; Mice; multidisciplinary; Neoadjuvant Therapy; Premenopause; Retrospective Studies; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08276-1

The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype 1 . 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 chemoresistance 2 , 3 – 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 induction 5 , 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. In three mouse models of breast cancer, we show reduced responses to neoadjuvant chemotherapy when treatment is initiated during the dioestrus stage, when compared with initiation during the oestrus stage.