Hormone therapy failure in human prostate cancer: Analysis by complementary DNA and issue microarrays

Background: The molecular mechanisms underlying the progression of prostate cancer during hormonal therapy have remained poorly understood. In this st udy, we developed a new strategy for the identification of differentially e xpressed genes in hormone-refractory human prostate cancer by use of a comb ination of complementary DNA (cDNA) and tissue microarray technologies, Met hods: Differences in gene expression between hormone-refractory CWR22R pros tate cancer xenografts (human prostate cancer transplanted into nude mice) and a xenograft of the parental, hormone-sensitive CWR22 strain were analyz ed by use of cDNA microarray technology. To validate the data from cDNA mic roarrays on clinical prostate cancer specimens, a tissue microarray of spec imens from 26 prostates with benign prostatic hyperplasia, 208 primary pros tate cancers, and 30 hormone-refractory local recurrences was constructed a nd used fur immunohistochemical detection of protein expression. Results: A mong 5184 genes surveyed with cDNA microarray technology, expression of 37 (0.7%) was increased more than twofold in the hormone-refractory CWR22R xen ografts compared with the CWR22 xenograft; expression of 135 (2.6%) genes w as reduced by more than 50%. The genes encoding insulin-like growth factor- binding protein 2 (IGFBP2) and 27-kd heat-shock protein (HSP27) were among the most consistently overexpressed genes in the CWR22R tumors. Immunohisto chemical analysis of tissue microarrays demonstrated high expression of IGF BP2 protein in 100% of the hormone-refractory clinical tumors, in 36% of th e primary tumors, and in 0% of the benign prostatic specimens (two-sided P =.0001). Overexpression of HSP27 protein was demonstrated in 31% of the hor mone-refractory tumors, in 5% of the primary tumors, and in 0% of the benig n prostatic specimens (two-sided P =.0001), Conclusions: The combination of cDNA and tissue microarray technologies enables rapid identification of ge nes associated with progression of prostate cancer to the hormone-refractor y slate and may facilitate analysis of the role of the encoded gene product s in the pathogenesis of human prostate cancer.