These data demonstrate that progesterone, at a physiologic dose, is a potent mediator of breast tumor cell proliferation (independent of estrogen) in a model system that maintains breast tumor 3D structure, microenvironment, and epithelial cell polarity (known factors required for PR expression and paracrine actions [59, 60]) and indicate that PR-dependent transcriptional programs (i.e., that drive proliferation) including those enacted by MAPK-dependent phosphorylation of PR on Ser294 are likely to be activated in human breast cancers cultured ex vivo. The gene discussed is PGR; the disease is breast cancer.