Abstract
BackgroundAlthough docetaxel-based chemohormonal therapy (CHT) is one of the standard treatments for castration-resistant prostate cancer (CRPC), pertinent biomarkers and precise mechanisms involved in the resistance for CHT for CRPC remain unknown. We investigated the relationship between chemohormonal resistance and the expression of steroid receptors and Hippo pathway proteins using a docetaxel-resistant prostate cancer (PCa) cell line and human PCa tissues in patients who underwent surgery with and without neoadjuvant therapy.MethodsA docetaxel-resistant subline (22Rv1-DR) was generated to assess Hippo pathway protein expression and the effect of YAP1 inhibition on cellular characteristics. A tissue microarray with 203 cores from 70 high-risk localized PCa tissues was performed to assess steroid receptor and Hippo pathway protein expressions.ResultsNuclear YAP (nYAP) expression was higher in 22RV-1-DR than in parental 22Rv-1 and YAP1 knockdown suppressed cell proliferation of 22Rv1-DR. Steroid receptor and Hippo pathway protein expressions varied among three different neoadjuvant groups, and nYAP1 expression was the highest in the CHT group. The patients with high nYAP in residual cancer after neoadjuvant CHT had a significantly higher biochemical recurrence (BCR) rate than those with low nYAP1. On multivariate analysis, the high nYAP1 was an independent prognostic factor for BCR.ConclusionsnYAP expression is a potential biomarker in high-risk patients treated with docetaxel-based CHT. Steroid receptors and Hippo pathway proteins may play a role in the chemohormonal resistance in advanced PCa.
Highlights
Docetaxel-based chemohormonal therapy (CHT) is one of the standard treatments for castration-resistant prostate cancer (CRPC), pertinent biomarkers and precise mechanisms involved in the resistance for CHT for CRPC remain unknown
We previously reported the outcomes of neoadjuvant chemohormonal therapy (CHT) combined with androgen deprivation therapy (ADT), docetaxel, and estramustine phosphate, followed by radical prostatectomy (RP) [7, 8]
We found the limitation of the effect of CHT in patients with high-risk localized prostate cancer (PCa), indicating the importance of elucidating the molecular mechanisms underlying the resistance to docetaxel–CHT to overcome resistance and improve the outcome for the treatment of high-risk localized PCa
Summary
Docetaxel-based chemohormonal therapy (CHT) is one of the standard treatments for castration-resistant prostate cancer (CRPC), pertinent biomarkers and precise mechanisms involved in the resistance for CHT for CRPC remain unknown. We previously reported the outcomes of neoadjuvant chemohormonal therapy (CHT) combined with ADT, docetaxel, and estramustine phosphate, followed by radical prostatectomy (RP) [7, 8]. In these studies, we found the limitation of the effect of CHT in patients with high-risk localized PCa, indicating the importance of elucidating the molecular mechanisms underlying the resistance to docetaxel–CHT to overcome resistance and improve the outcome for the treatment of high-risk localized PCa
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