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

Myungsun Shim,Yunlim Kim,Hanjong Ahn,Yangsoon Park

doi:10.1038/s41598-019-53280-5

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.

Highlights

In addition to AR splice variant formation, previous studies have suggested that abnormal hyperactivation of glucocorticoid(GR) signalling contributes to the progression of hormone-dependent prostate cancer (Pca) to castration-resistant Pca (CRPC) in patients receiving ADT10,11
We found that AR splice variant 7 (ARV7) transcript levels in human Pca tissue increased as the tumor progressed from hormone-naïve Pca to advanced Pca and to CRPC
ARV7 transcript levels increased at every stage from ADT administration, to tumors becoming resistant to ADT and to chemotherapy administration, the increase during the last stage was the greatest (p = 0.040, Fig. 1a)

Summary

Introduction

In addition to AR splice variant formation, previous studies have suggested that abnormal hyperactivation of glucocorticoid(GR) signalling contributes to the progression of hormone-dependent Pca to CRPC in patients receiving ADT10,11. Glucocorticoids are known to produce some beneficial effects by acting as a pituitary suppressant that reduces adrenal androgen production1,the GR signalling pathway may play a different role in CRPC by promoting cancer progression through enhancement of the expression of certain pro-inflammatory cytokines, such as interleukin-610,12. T1b prostate cancer (Pca); Group 2, hormone-sensitive and advanced/metastatic Pca; Group 3, chemo-naïve castration-resistant Pca (CRPC); Group 4, CRPC with chemotherapy.Values are presented as mean ± standard deviation or number (%). PSA, prostate-specific antigen; ADT, androgen deprivation therapy. AMeasured within 1 week of surgery bExcluded patients without androgen deprivation therapy to ADT and chemotherapy, using tissues obtained from human surgical specimens. We evaluated the association between the transcript levels of each receptor and the durations of ADT as well as clinical outcomes

Objectives

Methods

Results

Conclusion