Towards personalized endocrine prevention of breast cancer progression

Breast cancer (BC) is the most commonly diagnosed cancer and a leading cause of cancer-related mortality among women worldwide. Approximately 70% of cases are hormone receptor-positive (HR+), with endocrine therapies targeting the estrogen receptor (ER) used as the primary modality of treatment. While endocrine therapy have improved clinical outcomes, therapeutic resistance and disease recurrence remain major challenges. These limitations show the need to better understand the roles of other HRs, such as progesterone (PR) and androgen (AR) receptors, which are frequently co-expressed in HR+ tumors but their contribution to disease advancement is not yet comprehensively defined. To investigate the heterogeneity of HR signaling in HR+ BC, we combined in vitro, ex vivo, and in vivo models, including patient-derived xenografts (PDXs) and the mouse intraductal (MIND) model. Through genetic and pharmacological perturbations of ER, PR, and AR signaling, we demonstrate that individual HR+ BC models display distinct dependencies on specific HRs. While some models rely on ER, others show sensitivity to PR or AR modulation. Additionally, simultaneous targeting of multiple hormone receptors yields enhanced anti-tumor effects compared to single-agent strategies. We further validate the MIND model as a translational platform by showing that it recapitulates patient-specific treatment responses and reproduces postmenopausal hormonal profiles, confirmed by optimized liquid chromatography-mass spectrometry (LC-MS) hormone quantification. These findings highlight the complex and context-dependent nature of hormone signaling in BC and propose new opportunities for personalized therapeutic strategies in HR+ disease.