BERKELEY, CA (UroToday.com) - Many genetic-susceptibility loci for hereditary prostate cancer have been identified, but little is known about their role in disease progression or their association with tumor aggressiveness and patient mortality. In a pioneering study in 1941, Huggins et al. leveraged the known dependence of the growth and maintenance of the prostate gland on androgens such as dihydrotestosterone (DHT), and used orchidectomy (surgical removal of testicles and spermatic cord) to treat 21 patients who had metastases of local extension of PCa outside the capsule of the prostate. Strikingly, the clinical condition of most patients with advanced disease improved significantly following castration, paving the way for androgen deprivation therapy (ADT), the modern-day castration treatment. Although ADT effectively reduces the tumor burden in patients who harbor advanced disease, as well as in those that relapse following a successful radical prostatectomy and/or radiotherapy treatment, eventually most patients relapse and develop an incurable castration-resistant metastatic prostate cancer (CRMPC).
A critical side effect of ADT is the emergence of a compensatory mechanism that re-establishes androgen receptor (AR) activation / signaling within a subset of cancer cells and ultimately restores tumor growth. Perhaps the most common mechanism is the amplification of AR gene copy number, which is observed in about a third of CRMPCs, but not in hormone-naïve primary tumors. Although AR amplification is a direct consequence of ADT, other copy number alterations (CNAs) are also frequently observed in PCa; importantly, these CNAs are associated with corresponding changes in gene expression in 85% to 95% of cases.
We aimed to identify other CNAs associated with AR amplification that would facilitate the escape from ADT and lead to CRMPC. Surprisingly, we found that the hereditary prostate cancer genetic-susceptibility locus on chromosome 20 (HPC20) is one of a few loci that are significantly co-amplified with AR in CRMPC. Further characterization of the 20q13 common amplified region (CAR) revealed intricate AR-regulation of the locus, suggesting a synergistic interaction in tumors that harbor co-amplification of the 20q13 CAR with AR. We have described such a tumor-promoting functional link between the AR and the protein tyrosine phosphatase 1B (encoded by PTPN1 and located within the 20q13 CAR), and found that this role is dependent on AR-activity in androgen-dependent cells.
Earlier sequencing efforts have yielded a tremendous amount of data, which are now readily available for researchers around the globe. However, additional efforts are needed to unravel the specific role of CNAs, or the numerous single-nucleotide polymorphisms (SNPs) that have been identified by genome-wide association studies (GWAS). An impressive example of such efforts is the recent paper by Huang et al., in which rs339331, a prostate cancer risk-associated SNP at 6q22, was characterized as a functional HOXB13-binding site. These authors showed that increased HOXB13 binding to the rs339331 SNP, which acts as a transcriptional enhancer, leads to the over-expression of the associated RFX6 transcription factor gene, thereby increasing tumorigenicity.
Because the 20q13 CAR also encodes two transcription factors (SNAI1, CEBPB) plus a microRNA (MIR645), it is tempting to speculate that frequent co-amplification of AR with the 20q13 CAR leads to critical transcriptional rewiring in CRMPC. Validation of this hypothesis could provide a relevant biomarker of prognosis, and also attractive therapeutic targets for more than 35% of CRMPC patients that bear the AR / 20q13 CAR co-amplification.
- Huggins C, Stevens RE, Hodges CV. Studies on prostate cancer II The effects of castration on advanced carcinoma of the prostate gland. Arch Surg-Chicago 1941; 43: 209-223.
- Tang YC, Amon A. Gene copy-number alterations: a cost-benefit analysis. Cell 2013; 152: 394-405.
- Labbé DP, Nowak DG, Deblois G, Lessard L, Giguère V, Trotman LC et al. Prostate cancer genetic-susceptibility locus on chromosome 20q13 is amplified and coupled to androgen receptor-regulation in metastatic tumors. Mol Cancer Res 2014; 12: 184-189.
- Lessard L, Labbé DP, Deblois G, Bégin LR, Hardy S, Mes-Masson AM et al. PTP1B is an androgen receptor-regulated phosphatase that promotes the progression of prostate cancer. Cancer Res 2012; 72: 1529-1537.
- Huang Q, Whitington T, Gao P, Lindberg JF, Yang Y, Sun J et al. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nat Genet 2014; 46: 126-135.
David P. Labbé, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Harvard Medical School
Dana-Farber Cancer Institute
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