Identification of differentially expressed genes associated with androgen-independent growth of prostate cancer

BACKGROUND. The human prostate cancer xenograft, CWR22, similar to most human prostate cancers, regresses after castration and recurs several months after the removal of androgen. Genes uniquely associated with proliferation were identified by comparison of tumors that exist in androgen absence but differ in proliferative capacity. METHODS. cDNA libraries from CWR22 tumors from 20-day castrate mice (proliferation undetectable) and recurrent CWR22 tumors (proliferation rate similar to androgen-dependent CWR22) were compared to evaluate the possibility that proliferation is triggered by either gain of function or loss of suppression. Differentially expressed genes were evaluated further for their temporal association with the onset of cellular proliferation using northern and western analysis and immunohistochemistry of a series of CWR22 tumors that spanned the transition from androgen-dependent to recurrent growth. RESULTS. Subtractive hybridization identified 11 candidate genes from among 1,057 clones examined. Northern analysis confirmed differential expression of 8 genes. Western analysis revealed an association between tomoregulin, translation elongation factor-1α (EF-1α), Mxi-1, and thioredoxin-binding protein 2/vitamin D up-regulated protein, and the onset of recurrent growth. Immunohistochemistry revealed expression of tomoregulin, EF-1α, Mxi-1, and thioredoxin reductase-1 coincidental with the onset of cellular proliferation on day 120 after castration. CONCLUSIONS. One or more of these genes may represent an appropriate target to prevent, delay or treat recurrent prostate cancer.