Taxane-based Chemotherapy Induced Androgen Receptor Splice Variant 7 in Patients with Castration-Resistant Prostate Cancer: A Tissue-based Analysis

Abstract

In total, 95 prostate cancer (Pca) patients who underwent transurethral resection of the prostate from 2000 to 2013 were assigned to four groups: Group 1, hormone-naïve and T1a or T1b Pca (n = 17); Group 2, hormone-sensitive and metastatic Pca (n = 33); Group 3, chemo-naïve castration-resistant Pca (CRPC), (n = 18); and Group 4, CRPC with chemotherapy (n = 27). Full-length androgen receptor (ARfl) transcript levels significantly increased from Group 1 through to Group 3 (p = 0.045), but decreased from Group 3 through to Group 4. AR splice variant 7 (ARV7) and glucocorticoid receptor (GR) transcript levels significantly increased from Group 1 through to Group 4 (p = 0.002 and 0.049, respectively). Kaplan–Meier curve revealed that the high transcript level of these three receptors resulted in significantly poorer cancer-specific survival (CSS) than that by low transcript level, although Cox regression analysis revealed that the ARV7 level alone was an independent prognostic factor for CSS in CRPC patients (high vs. low: hazard ratio, 1.897; 95% confidence interval, 1.102–3.625; p = 0.042). In conclusion, ARV7 and GR transcript levels significantly increase as Pca progresses to CRPC.

Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance

“…The resistant phenotype was also validated in 22rv1 cells by the elevated expression (2.2-fold) of AR-V7 in 22rv1-DR cells compared to the parental cells ( Figure S1F ). This is consistent with a previous report that AR-V7 expression increases after chronic DTX exposure [ 52 ]. In addition, 22rv1-DR and PC3-DR cells grown under standardcell culture media supplemented with FBS showed increased total GR and β-catenin expression compared to their corresponding DTX-sensitive cell lines, whereas DU145-DR cells expressed lower total GR and β-catenin levels than their DTX-sensitive counterparts ( Figure 1 C,D).…”

Inhibition of the serine/threonine kinase BUB1 reverses taxane resistance in prostate cancer

“…Since we previously identified BUB1 as part of an AR-V7 driven network 14 and AR-V7 is associated with the development of taxane resistance, 8 , 9 , 30 we evaluated AR-V7 expression in mCRPC patient samples and taxane resistant cells. AR-V7 expression was significantly upregulated after chemotherapy treatment compared to non-treated patients ( Figure 5 A).…”

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

“…These observations suggest the existence of common mechanisms underlying therapy cross-resistance in mCRPC. These may include, for instance, the reactivation by ARSI treatment of AR variants such as AR-V7, which has been shown to contribute to ARSI resistance and is induced by taxanes in mCRPC cells and tissues [ 11 , 25 ]. However, clinically, AR-V7 does not appear to be essential for taxane chemoresistance since no correlation was found between AR-V7 expression and response to taxanes in patients with PCa [ 92 , 93 , 94 ].…”

“…Corticosteroids may influence PCa cell proliferation in a context-dependent manner by activating mutated (L702H) androgen receptor (AR), thus promoting mCRPC progression and therapy resistance [ 7 , 8 , 9 ]. The upregulation of AR splice variants such as AR-V7 has also been shown to contribute to resistance to both ARSI and chemotherapy in mCRPC [ 10 , 11 ]. Further, mCRPC cells treated with enzalutamide and abiraterone upregulate glucocorticoid receptor (GR) expression, and GR signaling leads to the transactivation of shared AR target genes, thus bypassing AR blockade [ 12 , 13 , 14 , 15 ].…”