Dataset Information

MicroRNAs and Androgen Receptor 3' Untranslated Region: A Missing Link in Castration-resistant Prostate Cancer?

ABSTRACT: The ligand-activated transcription factor, androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Prostate cancer initiates as an androgen-dependent disease and further accumulation of multiple sequential genetic and epigenetic alterations transform it into an aggressive, castration-resistant prostate cancer (CRPC). The molecular basis of the transition from androgen-dependent prostate cancer to CRPC remains unclear. However, it is apparent that AR plays a pivotal role in this alteration. The recent discovery that microRNAs (miRNAs) can target the function of AR suggests a functional role of these non-coding RNAs in the pathogenesis of prostate cancer. miRNAs usually function by targeting the 3' untranslated region (UTR) of a mRNA by base-pairing interactions and modulate translation either by destabilizing the message or by repression of protein synthesis in actively translating ribosomes. Here, we discuss the potential molecular pathways through which AR targeting miRNAs may promote CRPC. Modulation of AR expression by miRNAs presents a novel therapeutic option for prostate cancer, albeit it will likely be used in combination with the existing therapies.

SUBMITTER: Sikand K

PROVIDER: S-EPMC3315684 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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MicroRNAs and Androgen Receptor 3' Untranslated Region: A Missing Link in Castration-resistant Prostate Cancer?

Sikand Kavleen K Barik Sailen S Shukla Girish C GC

Molecular and cellular pharmacology 20110101 3

The ligand-activated transcription factor, androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Prostate cancer initiates as an androgen-dependent disease and further accumulation of multiple sequential genetic and epigenetic alterations transform it into an aggressive, castration-resistant prostate cancer (CRPC). The molecular basis of the transition from androgen-dependent prostate cancer to CRPC remains unclear. However, it is apparent that AR pla ...[more]

PMID: 22468168

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Project description:Plasma androgen receptor (AR) gain identifies metastatic castration-resistant prostate cancer (mCRPC) patients with worse outcome on abiraterone/enzalutamide, but its relevance in the context of taxane chemotherapy is unknown. We aimed to evaluate whether docetaxel is active regardless of plasma AR and to perform an exploratory analysis to compare docetaxel with abiraterone/enzalutamide. This multi-institutional study was a pooled analysis of AR status, determined by droplet digital polymerase chain reaction, on pretreatment plasma samples. We evaluated associations between plasma AR and overall/progression-free survival (OS/PFS) and prostate-specific antigen (PSA) response rate in 163 docetaxel-treated patients. OS was significantly shorter in case of AR gain (hazard ratio [HR]=1.61, 95% confidence interval [CI]=1.08-2.39, p=0.018), but not PFS (HR=1.04, 95% CI 0.74-1.46, p=0.8) or PSA response (odds ratio=1.14, 95% CI=0.65-1.99, p=0.7). We investigated the interaction between plasma AR and treatment type after incorporating updated data from our prior study of 73 chemotherapy-naïve, abiraterone/enzalutamide-treated patients, with data from 115 first-line docetaxel patients. In an exploratory analysis of mCRPC patients receiving first-line therapies, a significant interaction was observed between plasma AR and docetaxel versus abiraterone/enzalutamide for OS (HR=0.16, 95% CI=0.06-0.46, p<0.001) and PFS (HR=0.31, 95% CI=0.12-0.80, p=0.02). Specifically, we reported a significant difference for OS favoring abiraterone/enzalutamide for AR-normal patients (HR=1.93, 95% CI=1.19-3.12, p=0.008) and a suggestion favoring docetaxel for AR-gained patients (HR=0.53, 95% CI=0.24-1.16, p=0.11). These data suggest that AR-normal patients should receive abiraterone/enzalutamide and AR-gained could benefit from docetaxel. This treatment selection merits prospective evaluation in a randomized trial. PATIENT SUMMARY: We investigated whether plasma androgen receptor (AR) predicted outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel, and we performed an exploratory analysis in patients treated with docetaxel or AR-directed drugs as first-line mCRPC therapy. We showed that plasma AR normal favored hormonal treatment, whilst plasma AR-gained patients may have had a longer response to docetaxel, suggesting that plasma AR status could be a useful treatment selection biomarker.

Dataset Information

MicroRNAs and Androgen Receptor 3' Untranslated Region: A Missing Link in Castration-resistant Prostate Cancer?

Publications

MicroRNAs and Androgen Receptor 3' Untranslated Region: A Missing Link in Castration-resistant Prostate Cancer?

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