Abstract
Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation.
Highlights
Androgen receptor (AR) signaling activation plays an important role in the progression of metastatic castration-resistant prostate cancer (CRPC)
ARV7 amplicon was cloned into the pJET1.2/blunt vector in order to confirm its sequence in 22RV1 and in peripheral blood mononuclear cells (PBMC) from controls and CRPC patients
In this paper we report that ARV7 mRNA is not specific to prostate cancer but can be found in other types of cells normally express
Summary
Androgen receptor (AR) signaling activation plays an important role in the progression of metastatic castration-resistant prostate cancer (CRPC). Taxanes have shown an inhibitory effect over AR signaling apart from their anti-microtubule effect [5]. Active AR splicing variants have been identified as an important mechanism of the AR pathway activation in conditions of androgen depletion [6]. The most studied form has been the variant 7 (ARV7), which lacks the AR ligand-binding domain and is constitutively activated in absence of androgens [6]. Controversial studies report its role as a biomarker of taxane response [10,11,12,13]
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