Loss Of Id4 Initiates Pin-Like Lesions By Maintaining Stemness In Mice Prostate.

Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators, has emerged as a tumor suppressor in prostate cancer (PCa). Recent studies have shown that Id4 is highly expressed in the normal prostate and decreases in prostate cancer (PCa) due to epigenetic silencing. Id4 knockdown in androgen-sensitive LNCaP cells has been shown to lead to castration-resistant prostate cancer (CRPC) in vitro and in vivo. Id4-/- mice leads to underdeveloped prostate without the loss of androgen receptor (AR) expression. In this study we demonstrate that prostates from the Id4 knockout (Id4-/-) mice show PIN-like lesions, suggesting that loss of Id4 plays a major role in initiation of prostate PCa. Histology of Id4 -/- mice prostate shows more PIN lesions at 3 months and 6 months without showing clear evidence of prostate cancer. Immunohistochemical analysis demonstrated increased expression of Amacr, which is a biomarker for PIN and PCa, only in Id4-/- 3-month- and 6-month-old prostate tissue. The expression of Nkx3.1 and Pten tumor suppressor genes in Id4-/-mouse prostate was undetectable, suggesting that loss of Id4 has potential to initiate or progress to PCa. Although PTEN protein was not present in Id4-/- mice, the presence of the corresponding PTEN mRNA suggested intact transcriptional program. These results suggested that Id4 plays a role in regulating the translation of the PTEN mRNA. We are currently investigating the ID4-regulated mechanisms involved in the translational control of PTEN. The results suggested that id4-/- results in PIN lesions that are in part due to a block in Pten translation. Sca-1 is a member of the Ly6 family of glycosyl phostidylinositol (GPI)-anchored cell surface proteins used as stem cell marker in murine prostate. According to cancer stem cell theory, stem cells in basal layer of the prostate tubules give rise to transient amplifying cells and differentiate into terminally differentiated secretory luminal epithelial cells. From the same pathway it gives rise to the tumor-promoting cells, which ultimately form prostate cancer. Sca-1 is expressed in Id4-/- mice 3-month- and 6-month-old prostate glands. These data suggest that loss of Id4 can initiate PIN like lesions by maintaining stemness through regulating transcriptional, translational mechanism via altering the expression of PTEN, NKX3.1, C-MYC and other regulatory molecules. Currently we are investigating that regulatory mechanism, mainly focusing on mRNA interference mechanisms. Citation Format: Dhanushka Hewa Bostanthirige, Jugal Joshi, Shravan Kumar, Divya Patel, Jaideep Chaudhary. Loss of Id4 initiates PIN-like lesions by maintaining stemness in mice prostate [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A33.