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
Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Laboratory of Clinical Chemistry and Hematology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Nature. 2025 Jan;637(8044):195-204. doi: 10.1038/s41586-024-08276-1. Epub 2024 Dec 4.
The response of breast cancer to neoadjuvant chemotherapy (NAC) varies substantially, even when tumours belong to the same molecular or histological subtype. 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 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, 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.
乳腺癌对新辅助化疗（NAC）的反应差异很大，即使肿瘤属于相同的分子或组织学亚型。在这里，我们确定发情周期是导致这种异质性的一个重要因素。在三种乳腺癌小鼠模型中，我们发现与发情期开始治疗相比，在动情后期开始治疗时对NAC的反应降低。在人类患者的绝经前回顾性队列中也观察到了类似的结果。从机制上讲，动情后期表现出全身和局部的变化，包括：（1）经历上皮-间质转化的细胞数量增加，这与化疗耐药性有关；（2）肿瘤血管直径减小，提示对药物敏感性和递送存在潜在限制。此外，动情后期巨噬细胞的数量增加，巨噬细胞此前被认为与化疗耐药性的诱导有关。虽然NAC会扰乱发情周期，但巨噬细胞的这种高患病率仍然存在，而巨噬细胞的消耗减轻了在动情后期开始治疗时观察到的治疗反应降低的情况。我们的数据共同表明，发情周期是决定化疗敏感性的关键超日节律，值得未来开展临床研究，以利用最佳的治疗开始时间来提高化疗效果。
