In this study, we demonstrate that, in mammary and breast cancer cells, PRL/PRLR activates the apical-basal polarity cues and the Hippo signaling pathway, resulting in the suppression of the YAP-CCN2 oncogenic pathway that is critical in driving a differentiation program inducing/maintaining acinar morphogenesis, cell–cell junctions, limiting luminal-basal plasticity, and suppressing stemness. The gene discussed is PRL; the disease is breast cancer.