Relaxation of Insulin-Like Growth Factor II Imprinting in Prostate Cancer Development

: A marked propensity for prostate cancer to arises in the peripheral prostate with aging. The Insulin-like Growth Factor-II (IGF-II) gene is an auto-paracrine growth stimulator that is an important positive modulator of cancer development. lGF-II typically demonstrates monoallelic, or imprinted, expression in adult tissues and indeed this pattern is maintained in the periurethral zone, a region where cancer development is rare. In addition, IGF-II loss of imprinting (LOl), as well as increased lGF-II expression, are common attributes of prostate cancer. It is our hypothesis to be tested that an age-dependent loss of lGF-II imprinting, resulting from age-dependent changes in DNA methylation, occurs specifically in the peripheral zone of the prostate and contributes to the increased risk for cancer development. To examine temporally when this loss of IGF-II imprinting occurs and the mechanisms underlying it we propose 3 Specific Aims: (1) To determine if IGF-II LOl in the peripheral prostate derives from stromal and/or epithelial cells; (2) To determine whether lGF-II LOl occurs as an age-dependent process in human prostate tissues that are uninvolved with cancer; and (3) To examine DNA methylation as a mechanism for any observed changes in the imprint status in prostate tissues. This proposal is significant and unique in testing whether regional epigenetic changes occur in histologically normal prostate tissues that are destined to become neoplastic. We expect to determine whether specific age-related, peripheral zone changes in methylation and imprinting occur in the general population and whether these changes are linked to prostate cancer development.