Prostate Tumorigenesis Induced by PTEN Deletion Involves Estrogen Receptor beta Repression

Graphical Abstract Highlights d Prostate tumorigenesis caused by PTEN deletion involves loss of estrogen receptor b d ERb transcription is repressed by BMI-1, which is induced by PTEN deletion d ERb repression is needed for tumorigenesis because it enables HIF/VEGF signaling d HIF/VEGF signaling sustains BMI-1 expression, resulting in a positive feedback loop A causal role for ERb in prostate cancer has not been established. Mak et al. now show that loss of ERb occurs as a consequence of prostate tumorigenesis induced by PTEN deletion, and that this loss is necessary for tumorigenesis because it enables HIF/VEGF signaling in tumor cells. SUMMARY The role of ERb in prostate cancer is unclear, although loss of ERb is associated with aggressive disease. Given that mice deficient in ERb do not develop prostate cancer, we hypothesized that ERb loss occurs as a consequence of tumorigenesis caused by other oncogenic mechanisms and that its loss is necessary for tumorigenesis. In support of this hypothesis, we found that ERb is targeted for repression in prostate cancer caused by PTEN deletion and that loss of ERb is important for tumor formation. ERb transcription is repressed by BMI-1, which is induced by PTEN deletion and important for prostate tumorigenesis. This finding provides a mechanism for how ERb expression is regulated in prostate cancer. Repression of ERb contributes to tumorigenesis because it enables HIF-1/VEGF signaling that sustains BMI-1 expression. These data reveal a positive feedback loop that is activated in response to PTEN loss and sustains BMI-1.