Anti-progestin therapy targets hallmarks of breast cancer risk

• 成果类型: Article
• 署名作者: Simoes, Bruno M.; Pedley, Robert; McCloskey, Curtis W.; Roberts, Matthew; Reed, Austin D.; Twigger, Alecia-Jane; Tharmapalan, Pirashaanthy; Caruso, Amanda; Cabral, Sara; Wilby, Anthony J.; Harrison, Hannah; Zhou, Yuxi; Greenhalgh, Alice; Alghamdi, Suad A.; Forestiero, Martina; Lopez-Munoz, Jesica; Roche, Jasmin; Tuieng, Ren Jie; Khan, Muhammad A.; Squires, Steven; Astley, Susan M.; Harkness, Elaine F.; Santiago-Gomez, Angelica; Spence, Katherine; Ritchie, Jessica; Pritchard, Susan; Lim, Yit; Sherratt, Michael J.; Ando, Sebastiano; Howell, Anthony; Evans, D. Gareth; Gilmore, Andrew P.; Khaled, Walid T.; Khokha, Rama; Clarke, Robert B.; Howell, Sacha J.
• 署名单位: University of Manchester; University of Manchester; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Cambridge; University of Calabria; University of Manchester; University of Manchester; Manchester University NHS Foundation Trust; Wythenshawe Hospital NHS Foundation Trust; Wythenshawe Hospital; University of Manchester; University of Manchester; Christie NHS Foundation Trust
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09684-7
• 发表日期: 2025-12-18
• 关键词: MAMMOGRAPHIC DENSITY; cell-proliferation; RANK LIGAND; progesterone; MIFEPRISTONE; progenitors; prevention; platform; collagen; women

摘要

Breast cancer is the leading cause of cancer-related death in women worldwide1. 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 cancers2. 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 SOX9high 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.