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Anti-progestin therapy targets hallmarks of breast cancer risk

祖细胞 乳腺癌 医学 间质细胞 细胞外基质 癌症研究 孕酮受体 内科学 祖细胞 受体 肿瘤科 醋酸乌利司他 癌症 病理 内分泌学 细胞生长 临床试验 再生(生物学) 间充质干细胞 干细胞 生物信息学 乳腺组织 细胞 邻近连接试验
作者
Bruno M. Simões,Robert Pedley,Curtis W. McCloskey,Matthew Roberts,Austin D. Reed,Alecia‐Jane Twigger,Pirashaanthy Tharmapalan,Amanda Caruso,S. Cabral,A. Wilby,Hannah Harrison,Yuxi Zhou,Alice Greenhalgh,Suad A. Alghamdi,Martina Forestiero,Jesica Lopez-Muñoz,Jasmin Roche,Ren Jie Tuieng,M. Aurangzeb Khan,Steven Squires
出处
期刊:Nature [Nature Portfolio]
卷期号:648 (8094): 736-745 被引量:4
标识
DOI:10.1038/s41586-025-09684-7
摘要

Abstract Breast cancer is the leading cause of cancer-related death in women worldwide 1 . Here, in the Breast Cancer-Anti-Progestin Prevention Study 1 (BC-APPS1; NCT02408770 ), we assessed whether progesterone receptor antagonism with ulipristal acetate for 12 weeks reduces surrogate markers of breast cancer risk in 24 premenopausal women. We used multilayered OMICs and live-cell approaches as readouts for molecular features alongside clinical imaging and tissue micromechanics correlates. Ulipristal acetate reduced epithelial proliferation (Ki67) and the proportion, proliferation and colony formation capacity of luminal progenitor cells, the putative cell of origin of aggressive breast cancers 2 . MRI scans showed reduction in fibroglandular volume with treatment, whereas single-cell RNA sequencing, proteomics, histology and atomic force microscopy identified extracellular matrix remodelling with reduced collagen organization and tissue stiffness. Collagen VI was the most significantly downregulated protein after ulipristal acetate treatment, and we uncovered an unanticipated spatial association between collagen VI and SOX9 high luminal progenitor cell localization, establishing a link between collagen organization and luminal progenitor activity. Culture of primary human breast epithelial cells in a stiff environment increased luminal progenitor activity, which was antagonized by anti-progestin therapy, strengthening this mechanistic link. This study offers a template for biologically informed early-phase therapeutic cancer prevention trials and demonstrates the potential for premenopausal breast cancer prevention with progesterone receptor antagonists through stromal remodelling and luminal progenitor suppression.
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