Expression profiling of androgen target genes in prostate cancer

Abstract

Normal prostate epithelial cells are dependent on androgen for growth, differentiation and survival. A subset of prostate tumors is similarly dependent on androgen, and androgen ablation therapy typically results in the stasis or regression of these tumors. However, hormone-independent clones commonly arise following androgen ablation, and these clones typically display a more aggressive, less differentiated phenotype. Hormone-independent tumors retain androgen receptor (AR) expression. This observation suggests that these tumors may still require AR signaling, although in an androgen-independent manner. This hypothesis is supported by the observation that serum prostate-specific antigen levels increase in hormone-independent cancer despite the absence of androgen. We propose that additional AR targets are necessary for mediating tumor progression, in both hormonedependent and-independent states. We have stimulated androgen-responsive LAPC4 cells with androgens, and we have used microarrays to identify additional androgen targets. These targets include transcription factors, growth factors, signaling molecules and cytoskeletal and metabolic proteins. The in vivo androgen dependence of these targets has been confirmed in xenograft models. We are now using laser capture microdissection and the polymerase chain reaction with reverse transcription (Taqman) to quantify target gene expression in benign and malignant prostate epithelia from multiple patients. We are clustering tumor samples based on their AR target gene expression profiles in order to identify subsets of genes that are misexpressed in tumors relative to benign tissues, are expressed in androgen-independent tumors and correlate with biochemical failure of radical prostatectomy (as determined by rising prostate-specific antigen levels after surgery).

Characterization of a method for profiling gene expression in cells recovered from intact human prostate tissue using RNA linear amplification

“…Hepsin expression promotes prostate cancer metastasis, 31 and is high in prostate cancer as compared to normal prostate epithelial cells. 32 Independent investigations found b-microseminoprotein to be up in normal, and hepsin to be up in cancer, identical to findings in the current study. Importantly, confirmation of differential expression by independent investigators required analysis of large numbers of subject samples in each instance.…”

Gelatinase-mediated migration and invasion of cancer cells

“…Hepsin is a type II transmembrane serine protease normally expressed in hepatocytes (Leytus et al, 1988). Microarray analyses have consistently found it to be one of the most upregulated genes in advanced prostate cancer (Dhanasekaran et al, 2001;Magee et al, 2001). Other transmembrane serine proteases implicated in cancer progression are membrane-type serine protease-1/matriptase in breast cancer (Shi et al, 1993), TMPRSS2 in prostate cancer (Afar et al, 2001) and TMPRSS4 in pancreatic cancer (Gress et al, 1997).…”

GOLPH2 protein expression as a novel tissue biomarker for prostate cancer: implications for tissue-based diagnostics

“…Expression arrays, SNP analyses and mass spectrometry are new tools for biomarker identification (Zheng et al, 2007). Such high-throughput analyses have recently identified new prostate cancer biomarkers, including, for example, HEPSIN, EZH2 and a-methyl-Co-racemase (AMACR) (Dhanasekaran et al, 2001;Jiang et al, 2001;Luo et al, 2001;Magee et al, 2001;Stamey et al, 2001;Varambally et al, 2002;Rhodes et al, 2003;Parekh et al, 2007). AMACR has first been found upregulated in prostate cancer by Xu et al (2000) using suppressive subtractive hybridisation, and AMACR antibodies have become available quickly thereafter (Jiang et al, 2001;Rubin et al, 2002).…”