Taken together, our analyses show that STAT5 signaling spontaneously decreases in PRL-driven prostate tumors with aging and our results suggest that alternative compensatory pathways such as AKT and ERK1/2 signaling, but not STAT3 and AR signaling, promote prostate tumor progression upon hyper PRL signaling in the absence of STAT5. Here, PRL is linked to prostate neoplasm.