Prostate Tumorigenesis Induced by PTEN Deletion Involves Estrogen Receptor β Repression

• DOI: 10.1016/j.celrep.2015.02.063
• Publication Date: 2015-03-31T12:32:55Z
• Authors: Paul Mak; Jiarong Li; Sanjoy Samanta; Cheng Chang; D. Joseph Jerry; Roger J. Davis; Irwin Leav; Arthur M. Mercurio
• Keywords: Male; 0303 health sciences; and Hormone Antagonists; QH301-705.5; Cells; PTEN Phosphohydrolase; Prostatic Neoplasms; Cell Biology; Hormones; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Cell Line, Tumor; Hormone Substitutes; Animals; Estrogen Receptor beta; Humans; Biology (General); Cancer Biology; Signal Transduction

The role of ERβ in prostate cancer is unclear, although loss of ERβ is associated with aggressive disease. Given that mice deficient in ERβ do not develop prostate cancer, we hypothesized that ERβ 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 ERβ is targeted for repression in prostate cancer caused by PTEN deletion and that loss of ERβ is important for tumor formation. ERβ transcription is repressed by BMI-1, which is induced by PTEN deletion and important for prostate tumorigenesis. This finding provides a mechanism for how ERβ expression is regulated in prostate cancer. Repression of ERβ 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.