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Anti-progestin therapy targets hallmarks of breast cancer risk.

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Affiliations

  • 1. Manchester Breast Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
      Authors
    • Simões BM 1
    • Pedley R 1, 5
    • Roberts M 1
    • Caruso A 1, 8
    • Cabral S 1
    • Wilby AJ 1
    • Harrison H 1
    • Zhou Y 1, 5
    • Greenhalgh A 1
    • Alghamdi SA 1
    • Forestiero M 1, 8
    • Lopez-Muñoz J 1
    • Roche J 1
    • Astley SM 1, 6
    • Santiago-Gómez A 1
    • Spence K 1
    • Howell A 1, 7
    • Gilmore AP 1, 5
    • Clarke RB 1
    • Howell SJ 1, 7
    (20 authors)
  • 2. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
      Authors
    • McCloskey CW 2
    • Tharmapalan P 2
    • Khokha R 2
    (3 authors)
  • 3. Department of Pharmacology, University of Cambridge and Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, UK.
      Authors
    • Reed AD 3
    • Twigger AJ 3
    • Khaled WT 3
    (3 authors)
  • 4. Division of Cell Matrix Biology & Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
      Authors
    • Tuieng RJ 4
    • Sherratt MJ 4
    (2 authors)
  • 5. Manchester Cell-Matrix Centre, University of Manchester, Manchester, UK.
      Authors
    • Pedley R 1, 5
    • Zhou Y 1, 5
    • Khan MA 5
    • Gilmore AP 1, 5
    (4 authors)
    • Show all (8)

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Nature, 05 Nov 2025, 648(8094):736-745
https://doi.org/10.1038/s41586-025-09684-7 PMID: 41193807 PMCID: PMC12711567

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
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Abstract 

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.

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    Funding 

    Funders who supported this work.

    Breast Cancer Now (1)

    National Institute for Health Research (NIHR) (1)

    Wellcome Trust (1)

    • Grant ID: 226804/Z/22/Z

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