The oestrous cycle stage affects mammary tumour sensitivity to chemotherapy

• 成果类型: Article
• 署名作者: 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; Delgado, Eulalia Noguera; 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
• 署名单位: Netherlands Cancer Institute; Netherlands Cancer Institute; Netherlands Cancer Institute; Flanders Institute for Biotechnology (VIB); KU Leuven; Netherlands Cancer Institute; Netherlands Cancer Institute; Netherlands Cancer Institute; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Netherlands Cancer Institute; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Netherlands Cancer Institute; Utrecht University; Netherlands Cancer Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1559
• DOI: 10.1038/s41586-024-08276-1
• 发表日期: 2025-01-02
• 关键词: metastatic breast-cancer; induced amenorrhea; menstrual-cycle; cell-proliferation; ovarian cycle; phase; MODEL; gland; progesterone; expression

摘要

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, 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 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.