Reverse phase
protein microarray technology was used to study key signaling pathways thought to be involved in the progression of benign epithelium to the lethal phenotype of
prostate cancer. Specimens of
androgen-stimulated localized
prostate cancer (N = 21) and
androgen-deprivation
therapy-recurrent local (N = 4) or metastatic (N = 11)
prostate cancer were
laser capture microdissected prior to analysis. The results showed significant increases in
protein expression levels in malignant epithelial cells and patient-matched stromal tissue, which included higher levels of the apoptotic
proteins Bax and Smac/Diablo and increased phosphorylation of Bcl2 (S70). The
mitochondrial protein Smac/Diablo and the transcription regulatory
protein STAT3 (Y705) correlated with Gleason sum and differed statistically in high Gleason grade (8-10)
prostate cancers. Distinct
metastasis-specific pathways were activated by
caspase cleavage activation, ErbB2 phosphorylation, Bax total
protein and Bcl-2 phosphorylation while phosphorylation of all three members of the MAPK family, ERK, p38, and SAP/JNK, were reduced significantly in metastatic lesions compared to primary
cancers. This study, the most comprehensive pathway analysis ever performed for human
prostate cancer, presents evidence of specific pathway
biomarkers that may be useful for assessment of prognosis and stratification for
therapy if validated in larger clinical study sets.