Mice that had completed a pregnancy, 3 weeks of lactation, and 2 months of involution were injected with RCAS-caErbb2. 3 weeks later, the resulting lesions were compared with those in age-matched virgin controls for pSTAT5 (A), apoptosis (via TUNEL) (B), and Ki67 (C and E). Levels of apoptosis (B) and proliferation in normal ducts (D) of uninfected mice are shown for comparison. Columns represent the mean, and error bars the SEM. Student’s t test measured p values. n = 5 mice. (F) Schematic Model. Breast cells with oncogenic activation (red) progress to cancer slowly due to the apoptosis anticancer barrier. However, with a pregnancy, these preexisting precancerous cells activate PRLR-Jak2-STAT5 signaling (becoming pink), and maintain the activated state of this pathway even at involution likely through oncoprotein-initiated phosphorylation and inactivation of GSK3β. pSTAT5 overcomes both the apoptosis anticancer barrier and the apoptotic force unleashed by involution, consequently accelerating progression to malignancy.