Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in males. Although the different stages of prostate cancer have been well defined histologically, the molecular mechanisms underlying prostate cancer development remain relatively unknown. PTEN mutation and deletion play an important role in human prostate cancer. Murine Pten prostate cancer model established in our lab not only mimics the course of human prostate cancer development but also share some signature gene profile changes with human prostate cancer. The gene expression data from our murine Pten model indicated that Nkx3.1 expression is consistently decreased or lost in PIN (prostatic intraepithelial neoplasia, PIN) as well as cancers. To address the functional role of Nkx3.1, we overexpressed Nkx3.1 in Pten null epithelium derived from different stages of tumorigenesis and tested its effects on prostate cancer initiation and progression. Our study demonstrates that forced Nkx3.1 expression via lentivirus-mediated gene transfer could reverse tumor initiation from hyperplasia to PIN lesion. However, Nkx3.1 overexpression only delays tumor initiation if Pten null epithelial cells are derived from PIN lesions, suggesting additional genetic alterations, beside Nkx3.1 down-regulation, may have occurred in Pten null prostate gland from hyperplasia to PIN stage. The molecular mechanisms involved in the phenotype reversion will be discussed.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]