The ovarian hormone progesterone is a critical regulator of normal epithelial development in the breast. Acting through its nuclear receptors PRA and PRB, which form functionally distinct hetero- and homodimers, progesterone regulates the transcription of a suite of developmental and proliferative genes to mediate the formation of new branching ductal structures in the developing breast during pregnancy and the luteal phase of each menstrual cycle. In normal tissues, PRA and PRB are equivalently expressed and are assumed to act primarily as a heterodimer. However, in breast cancer, PRA commonly becomes predominant, and over-expression of this isoform is associated with a poorer outcome. Progesterone treatment of primary normal breast organoids increases DNA replication licensing and cell cycle activity, to increase progenitor cell numbers. Single cell profiling of normal breast organoids after treatment confirmed this effect and suggested direct stimulation of the progenitor compartment. We hypothesized that in the malignant setting, changes to PR isoform level and chromatin organisation combine to result in aberrant transcriptional regulation, leading to deleterious activation of stem and proliferation pathways in breast cancer. Modulating the balance between PRA and PRB in breast cancer cell models, we used ChIP-seq and ATAC-seq to investigate the relative influence of the two isoforms on progesterone regulation of transcriptional markers of progenitor activity. We found that predominant or exclusive expression of PRA resulted in a marked expansion of the progesterone regulated cistrome. Moreover, PRA bound substantially more frequently and with lower fidelity to non-canonical PR binding sites to mediate abnormal transcriptional responses and regulation of a number of cancer stem cell markers. Taken together our data suggest that breast cancer cells exploit normal progesterone regulatory processes to stimulate expansion of lesions in the breast, corroborating the role of progesterone as a promoter of breast cancer progression.