ABSTRACT: Effective strategies for primary prevention of breast cancer in premenopausal women remain limited, largely due to the modest tolerability and uptake of existing endocrine interventions. In our recent study, we demonstrate that short-term antagonism of progesterone receptor (PR) signaling targets multiple biological determinants of breast cancer risk, including epithelial progenitor activity, extracellular matrix remodeling and tissue mechanics. In this Perspective, we reflect on the conceptual and translational implications of these findings. We discuss how progesterone-driven endocrine-mechanical feedback loops shape increased risk tissue states and how their pharmacological disruption enables coordinated attenuation of epithelial and stromal susceptibility. We further consider the integration of multi-omics profiling and imaging biomarkers as a framework for prevention trials. In fact, PR antagonism may represent a promising foundation for biomarker-guided risk-reduction approaches in younger women and highlight broader opportunities for targeting tissue architecture in cancer prevention.

Impact statement: Progesterone receptor antagonism targets drivers of breast cancer risk across epithelial and stromal tissue compartments, establishing a new approach to prevention in younger women.

Key words: Breast cancer prevention; progesterone receptor antagonists; mammographic density; extracellular matrix remodeling.