Anti-progestin therapy targets hallmarks of breast cancer risk
Breast cancer is the leading cause of cancer-related death in women worldwide<sup>1</sup>. 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<sup>2</sup>. 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<sup>high</sup> 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.
Authors
- Ren Jie Tuieng (ORCID: https://orcid.org/0000-0001-9019-7342)
- Alecia‐Jane Twigger (ORCID: https://orcid.org/0000-0003-4361-817X)
- Sacha J. Howell (ORCID: https://orcid.org/0000-0001-8141-6515)
- Curtis W. McCloskey (ORCID: https://orcid.org/0000-0002-3481-2221)
- Katherine Spence (ORCID: https://orcid.org/0000-0002-8137-165X)
- Andrew Gilmore (ORCID: https://orcid.org/0000-0002-9988-0436)
- Rama Khokha (ORCID: https://orcid.org/0000-0002-6028-1524)
- A. Wilby (ORCID: https://orcid.org/0009-0004-3165-9606)
- Walid T. Khaled (ORCID: https://orcid.org/0000-0001-9068-5776)
- Elaine F. Harkness (ORCID: https://orcid.org/0000-0001-6625-7739)
- Alice Greenhalgh
- Jessica Ritchie (ORCID: https://orcid.org/0009-0002-7432-8255)
- Michael J. Sherratt (ORCID: https://orcid.org/0000-0003-4759-6617)
- M. Aurangzeb Khan (ORCID: https://orcid.org/0000-0003-4341-6551)
- Robert Pedley (ORCID: https://orcid.org/0000-0002-0801-7240)
- Pirashaanthy Tharmapalan
- Susan Pritchard (ORCID: https://orcid.org/0000-0001-6209-6050)
- Robert B. Clarke (ORCID: https://orcid.org/0000-0001-5407-3123)
- Suad A. Alghamdi (ORCID: https://orcid.org/0000-0002-8325-5994)
- S. Cabral (ORCID: https://orcid.org/0009-0007-5164-6935)
- Austin D. Reed
- Steven Squires (ORCID: https://orcid.org/0000-0003-3681-1342)
- Amanda Caruso (ORCID: https://orcid.org/0000-0002-3254-5764)
- Angélica Santiago-Gómez (ORCID: https://orcid.org/0000-0002-2946-2669)
- Bruno M. Simões (ORCID: https://orcid.org/0000-0003-1253-6657)
- Jasmin Roche
- D. Gareth Evans (ORCID: https://orcid.org/0000-0002-8482-5784)
- Martina Forestiero (ORCID: https://orcid.org/0009-0003-3367-639X)
- Hannah Harrison (ORCID: https://orcid.org/0000-0002-0054-8047)
- Yuxi Zhou (ORCID: https://orcid.org/0000-0002-3700-1897)
- Matthew Roberts (ORCID: https://orcid.org/0000-0003-0659-7138)
- Sebastiano Andò
- Yit Yoong Lim
- Susan Astley (ORCID: https://orcid.org/0000-0002-2989-2765)
- Jesica Lopez-Muñoz (ORCID: https://orcid.org/0000-0002-5311-5579)
Institutions
- University Health Network (CA)
- University of Pittsburgh (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Manchester Academic Health Science Centre (GB)
- Wellcome Centre for Cell-Matrix Research (GB)
- Florence Nightingale Foundation (GB)
- Princess Margaret Cancer Centre (CA)
- University of Manchester (GB)
- Henry Royce Institute (GB)
- St Mary's Hospital (GB)
- Medicines Discovery Catapult (GB)
- UPMC Hillman Cancer Center (US)
- The Christie NHS Foundation Trust (GB)
- Wythenshawe Hospital (GB)
- University of Calabria (IT)
Publication Details
- Journal
- Nature
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1038/s41586-025-09684-7
- Citations
- 3
- Primary Topic
- Estrogen and related hormone effects
- Type
- article
- Field-Weighted Citation Impact
- 5.45