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Background  The ovarian hormones estrogen and progesterone (EP) are implicated in breast cancer causation. A specific consequence of progesterone exposure is the expansion of the mammary stem cell (MSC) and luminal progenitor (LP) compartments. We hypothesized that this effect, and its molecular facilitators, could be abrogated by progesterone receptor (PR) antagonists administered in a mouse model.    Methods  Ovariectomized FVB mice were randomized to 14 days of treatment: sham, EP, EP + telapristone (EP + TPA), EP + mifepristone (EP + MFP). Mice were then sacrificed, mammary glands harvested, and mammary epithelial cell lineages separated by flow cytometry using cell surface markers. RNA from each lineage was sequenced and differential gene expression was analyzed using DESeq. Quantitative PCR was performed to confirm the candidate genes discovered in RNA seq. ANOVA with Tukey post hoc analysis was performed to compare relative expression. Alternative splicing events were examined using the rMATs multivariate analysis tool.    Results  Significant increases in the MSC and luminal mature (LM) cell fractions were observed following EP treatment compared to control ( p  < 0.01 and  p  < 0.05, respectively), whereas the LP fraction was significantly reduced ( p  < 0.05). These hormone-induced effects were reversed upon exposure to TPA and MFP ( p  < 0.01 for both). Gene Ontology analysis of RNA-sequencing data showed EP-induced enrichment of several pathways, with the largest effect on  Wnt  signaling in MSC, significantly repressed by PR inhibitors. In LP cells, significant induction of  Wnt4  and  Rankl , and  Wnt  pathway intermediates  Lrp2  and  Axin2  (confirmed by qRTPCR) were reversed by TPA and MFP ( p  < 0.0001). Downstream signaling intermediates of these pathways  (Lrp5 ,  Mmp7 ) showed similar effects. Expression of markers of epithelial-mesenchymal transition ( Cdh1 ,  Cdh3 ) and the induction of EMT regulators ( Zeb1 ,  Zeb2 ,  Gli3 ,  Snai1 , and  Ptch2 ) were significantly responsive to progesterone. EP treatment was associated with large-scale alternative splicing events, with an enrichment of motifs associated with  Srsf ,  Esrp , and  Rbfox  families. Exon skipping was observed in  Cdh1 ,  Enah , and  Brd4 .    Conclusions  PR inhibition reverses known tumorigenic pathways in the mammary gland and suppresses a previously unknown effect of progesterone on RNA splicing events. In total, our results strengthen the case for reconsideration of PR inhibitors for breast cancer prevention.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13058-021-01455-2.

Progesterone receptor antagonists reverse stem cell expansion and the paracrine effectors of progesterone action in the mouse mammary gland