The transition from androgen-dependent to aggressive androgen-independent growth is an important development in prostate cancer, and the identification of genes expressed differentially between these two phenotypes could provide new therapeutic targets as well as prognostic markers. Using a subtractive approach designated linker capture subtraction, we have now isolated several genes expressed differentially between the human prostate carcinoma cell lines LNCaP and PC-3, which are androgen-dependent and androgen-independent, respectively. In addition to 10 known genes that may be involved in signal transduction, tumor growth, tumor invasion, and metastasis, 3 novel genes were isolated. One of these, designated NPG-1, was expressed by the majority of primary tumors examined. Moreover, the degree of NPG-1 expressed correlated with an aggressive histopathology.