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Abstract
BackgroundA significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC.MethodsWe analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry.ResultsAR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naïve tumours.ConclusionsAR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC.
Highlights
Prostate cancer (PC) is the most common malignancy and third most common cause of cancer-related death among men in Europe
androgen receptor (AR) mutations and copy-number variations (CNVs) are detected only in castrationresistant form of PC (CRPC) cases Since the mechanisms leading to emergence of CRPC are still largely unknown, we wanted to study the expression of AR splicing variants and other AR aberrations in tandem during different stages of prostate cancer (PC)
We show that even though AR-V3, AR-V7 and AR-V9 are expressed widely in different sample types, they are statistically more highly expressed in metastatic CRPCs in comparison to two hormone-naïve sample groups, prostatectomies and lymph node metastases
Summary
Prostate cancer (PC) is the most common malignancy and third most common cause of cancer-related death among men in Europe. Even though the exact mechanism by which CRPC develops remains to be fully understood, several mechanisms of castration resistance have been identified such as AR gene amplification,[1,2] point mutations in AR gene[3,4] and induction of steroidogenesis in CRPC cells.[5,6,7] AR gene amplification has been demonstrated in approximately 30% of CRPCs.[1] Cancers with AR amplification have been shown to respond better to second-line maximal androgen blockade compared to tumours without the amplification, the response was short-lived.[8] AR mutations are rare even at CRPC stage being present in approximately 10–30% of cases.[4] These mutations are almost always associated with diverse gains-of-function and about 45% of the mutations occur in the ligand-binding domain.[9] AR mutations can broaden ligand specificity to alternative steroid hormones, hypersensitise the receptor to castrate levels of androgens or lead to resistance to current forms of treatment making AR active even in the presence of anti-androgens.[10]. CONCLUSIONS: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC
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