Molecular Alterations in Primary Prostate Cancer after Androgen Ablation Therapy

• Published in: Clinical cancer research Vol. 11; no. 19; pp. 6823 - 6834
• Main Authors: BEST, Carolyn J. M, GILLESPIE, John W, GONZALEZ, Sergio, VELASCO, Alfredo, LINEHAN, W. Marston, MATUSIK, Robert J, PRICE, Douglas K, FIGG, William D, EMMERT-BUCK, Michael R, CHUAQUI, Rodrigo F, YAJUN YI, CHANDRAMOULI, Gadisetti V. R, PERLMUTTER, Mark A, GATHRIGHT, Yvonne, ERICKSON, Heidi S, GEORGEVICH, Lauren, TANGREA, Michael A, DURAY, Paul H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2005
• Subjects: Aged; Androgen Antagonists - metabolism; androgen-independent prostate cancer; Androgens - metabolism; Antineoplastic agents; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Biopsy; Cell Adhesion; Chromosome Deletion; Chromosome Mapping; Chromosomes - ultrastructure; Cluster Analysis; Disease Progression; Down-Regulation; Gene Deletion; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genome; Gynecology. Andrology. Obstetrics; Humans; Interleukin-6 - metabolism; laser capture microdissection; Lasers; Male; Male genital diseases; Medical sciences; microarrays; Middle Aged; Models, Statistical; Neoplasm Metastasis; Nephrology. Urinary tract diseases; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Pharmacology. Drug treatments; Principal Component Analysis; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; RNA - metabolism; RNA amplification; Signal Transduction; Tumors; Tumors of the urinary system; Up-Regulation; Urinary tract. Prostate gland; Urinary system disease; Treatment; Prostate disease; Androgen; Primary; Malignant tumor; Sex steroid hormone; Male genital diseases; Ablation; Prostate cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0585

Purpose: After an initial response to androgen ablation, most prostate tumors recur, ultimately progressing to highly aggressive androgen-independent cancer. The molecular mechanisms underlying progression are not well known in part due to the rarity of androgen-independent samples from primary and metastatic sites. Experimental Design: We compared the gene expression profiles of 10 androgen-independent primary prostate tumor biopsies with 10 primary, untreated androgen-dependent tumors. Samples were laser capture microdissected, the RNA was amplified, and gene expression was assessed using Affymetrix Human Genome U133A GeneChip. Differential expression was examined with principal component analysis, hierarchical clustering, and Student's t testing. Analysis of gene ontology was done with Expression Analysis Systematic Explorer and gene expression data were integrated with genomic alterations with Differential Gene Locus Mapping. Results: Unsupervised principal component analysis showed that the androgen-dependent and androgen-independent tumors segregated from one another. After filtering the data, 239 differentially expressed genes were identified. Two main gene ontologies were found discordant between androgen-independent and androgen-dependent tumors: macromolecule biosynthesis was down-regulated and cell adhesion was up-regulated in androgen-independent tumors. Other differentially expressed genes were related to interleukin-6 signaling as well as angiogenesis, cell adhesion, apoptosis, oxidative stress, and hormone response. The Differential Gene Locus Mapping analysis identified nine regions of potential chromosomal deletion in the androgen-independent tumors, including 1p36, 3p21, 6p21, 8p21, 11p15, 11q12, 12q23, 16q12, and 16q21. Conclusions: Taken together, these data identify several unique characteristics of androgen-independent prostate cancer that may hold potential for the development of targeted therapeutic intervention.