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BC-APPS1: Anti-progestin therapy targets hallmarks of breast cancer risk through epithelial-stromal remodelling

ABSTRACT: Breast cancer (BC) is the leading cause of women's cancer death worldwide. Here, in the BC – Anti Progestin Prevention Study 1 (BC-APPS1; NCT02408770), we assess whether progesterone receptor antagonism with ulipristal acetate (UA) for 12 weeks reduces surrogate markers of BC risk in 24 premenopausal women. We employ a multi-layered OMICs and live-cell approach as readouts for molecular features alongside clinical imaging and tissue micro-mechanics correlates. UA reduced epithelial proliferation (Ki67) and the proportion, proliferation, and colony formation capacity of luminal progenitor (LP) cells, the precursors of aggressive BCs. MRI scans showed reduction in fibroglandular volume with treatment, while single-cell RNAseq, proteomics, histology and atomic force microscopy identified extracellular matrix remodelling with reduced collagen organisation and tissue stiffness. Laser capture targeted mass spectrometry revealed Ccollagen VI as the most significantly down-regulated protein after UA treatment and we uncovered an unanticipated spatial association between Collagen VI and Sox9hi LP cell localization, establishing a link between collagen organization and LP activity. This study offers a template for molecularly informed early phase prevention trials and demonstrates the potential for premenopausal BC prevention with progesterone receptor antagonists through stromal remodelling and LP suppression.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Lobe

SUBMITTER: Andrew Gilmore

LAB HEAD: Andrew Gilmore

PROVIDER: PXD067122 | Pride | 2025-09-04

REPOSITORIES: Pride

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			Action	DRS
	P06Post_E02.raw	Raw
	P06Pre_E01.raw	Raw
	P12Post_E04.raw	Raw
	P12Pre_E03.raw	Raw
	P17Post_E06.raw	Raw

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