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Gene expression changes during hormonal therapy for prostate cancer reveal candidate diagnostic and drug targets

Although prostate cancers initially respond favorably to androgen deprivation, regrowth of androgen-independent tumors is very common. The molecular mechanisms involved in the regression and regrowth of prostate cancers are unknown. We applied complementary DNA microarrays containing 6,605 genes to identify gene expression changes in the CWR22 human prostate cancer xenograft model system 12 h to 16 d after androgen deprivation, as well as in recurrent androgen-independent CWR22R tumors. We identified 59 genes whose expression levels decreased threefold in response to castration, including several cell cycle regulators. In the recurrent tumors, expression levels of 57 of these genes (96.6%) were restored, suggesting reactivation of androgen signaling in the absence of ligand. Of the 6,605 genes, 251 (3.8%) were differentially expressed between primary and recurrent prostate cancers. These genes included those coding for transcription factors, signal transducers, growth and survival factor receptors and cell cycle regulators. One of the most overexpressed genes in the recurrent tumors was S100P, which encodes a calcium-binding signaling protein. The role of S100P in the progression of prostate cancers in vivo was further suggested by in situ hybridization of messenger RNA and protein immunostaining of 440 clinical tumor specimens in a tissue microarray format. Tissue microarray analysis indicated that S100P expression increased significantly (P<0.0001) during the progression of prostate cancers in vivo, with the highest levels seen in hormone-refractory and metastatic prostate cancers. The cDNA microarray data may also suggest targets for therapeutic intervention. For example, several direct and indirect rapamycin targets were differentially expressed in recurrent tumors. Rapamycin also inhibited CWR22R prostate cancer cell growth in vitro. Tissue and cDNA microarrays enable rapid identification, prioritization and validation of gene targets that may have diagnostic and therapeutic significance in the management of patients with hormone-refractory human prostate cancer. Hormone-independent prostate cancer growth seems to require re-expression of androgen-dependent signaling pathways as well as altered expression of several other genes.

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Mousses, S., Bubendorf, L., Kononen, J. et al. Gene expression changes during hormonal therapy for prostate cancer reveal candidate diagnostic and drug targets. Nat Genet 27, 75 (2001).

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