Our data provide insight into how progestin treatment may block proliferation in some strongly ER+/PR+ breast cancers (containing PRs capable of undergoing regulated SUMOylation, a modification that is primarily transcriptionally repressive at SR target genes and required to repress ER-alpha and other SR-dependent transcriptional events), while stimulating proliferation in others (containing modest levels of phosphorylated and SUMO-deficient PRs that are active drivers of unique cancer transcriptomes). Here, ESR1 is linked to cancer.