Hormone receptor signaling in estrogen receptor positive breast cancer

Estrogen receptor (ER) and progesterone receptor (PR) signaling tightly interact in controlling postnatal breast development and impinge on breast carcinogenesis. PR is a direct transcriptional target of ER signaling and ER and PR bind closely to DNA and interact physically. The clinical significance of their molecular interactions remains unclear as most studies are done using simplistic or non-physiological models. Here, we exploit intraductal xenografts of ER+ breast cancer (BC) cell lines and patient-derived tumor cells to study ER and PR signaling in physiological endocrine settings. Relative tumor growth stimulation by 17-β-estradiol (E2), progesterone (P4) and the combination of the two is cell line and PDX-dependent. Across all models both ER and PR are required for tumor growth. Ectopic PR expression restores growth in genetically or pharmacologically ER-ablated tumor cells and induces ER-dependent gene expression in MCF7 xenografts showing that PR mediates ER function. PR stimulates tumor growth and metastasis independent of ligand. In PDXs PR induction correlates with tumor growth. Our findings show differential hormone sensitivities of luminal BC and reveal PR as essential for hormone receptor positive tumor progression and suggest PR degradation as a therapeutic option for ER BCs.