Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models

• Published in: PloS one Vol. 5; no. 10; p. e13500
• Main Authors: Marques, Rute B, Dits, Natasja F, Erkens-Schulze, Sigrun, van Weerden, Wytske M, Jenster, Guido
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19-10-2010; Public Library of Science (PLoS)
• Subjects: Adaptation; Adaptations; Analysis; Androgen receptors; Androgens; Angiogenesis; Base Sequence; Biomarkers; Biotechnology; Bypasses; Cancer; Cancer treatment; Care and treatment; Cell culture; Cell death; Cell growth; Cell Line, Tumor; Cell migration; Cell survival; Deregulation; Disease Progression; DNA microarrays; DNA Primers; Down-Regulation; Gastric cancer; Gene expression; Gene Expression Profiling; Gene regulation; Genes; Genetics and Genomics/Gene Expression; Growth factors; Health aspects; Humans; Ligands; Male; Metastasis; Morphogenesis; Mutation; Oligonucleotide Array Sequence Analysis; Oncology/Multiple Endocrine Disorders and Neoplasias; Prostate cancer; Prostatic Neoplasms - diagnosis; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Pulmonary fibrosis; Receptors, Androgen - metabolism; Recurrence (Disease); Remission; Reproductive system; Reproductive systems; Reverse Transcriptase Polymerase Chain Reaction; Stomach cancer; Survival; Technology assessment; Therapy; Tumors; Urology; Urology/Prostate Cancer
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0013500

Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2.
Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10(-7)). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression.
Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.