SAT-328 Androgens Modulate the Expression of Prostatic Acid Phosphatase

Abstract

INTRODUCTION: Prostatic acid phosphatase (PAP) is an acid phosphatase synthesized in prostate epithelial cells that served as the biochemical diagnostic mainstay for prostate cancer for several decades. There are two forms of PAP, secretory(sPAP) and transmembrane (TM-PAP), that are derived from alternative transcripts of the gene. PAP is highly expressed by epithelial cells of the adult prostate, however, the androgenic regulation of prostatic acid phosphatase is not well understood. HYPOTHESIS AND OBJECTIVES: We hypothesized that androgens do not increase PAP expression. Our objectives were to determine the immunohistochemical expression of PAP in human fetal prostate tissue, human bone metastases, and intact and castrated xenograft tumors of human VCaP prostate cancer cells. In addition, the effects of dihydrotestosterone (DHT) onTM- and sPAP expression in vitro were quantified. METHODS: Immunohistochemical staining for PAP, androgen receptor (AR) and Prostate Specific Antigen (PSA) protein expression was carried out on human fetal prostate (9.5, 11.5, 13, 16.5 and 18 weeks of gestational age) and human castration-resistant prostate cancer bone metastases archival specimens obtained with IRB approval. Tissue from human benign prostate and breast cancer metastases were used as controls. For xenograft studies, VCaP cells were inoculated subcutaneously into SCID mice and surgical or sham castration was performed after tumor development. Mouse tumors and weights were measured biweekly and tumor tissue isolated after mouse sacrifice. Isolated tumors were stained for PAP, AR and PSA. RESULTS: PAP expression was an early marker of prostate development and observed in the fetal prostate as early as 11.5 weeks of gestational age. Strong PAP expression was observed in all human castration-resistant prostate cancer bone metastases examined (4/4 specimens). The AR was absent in two of four specimens. PSA was expressed in human castration-resistant bone metastatic prostate specimens; however, the expression was not as strong as PAP. In vivo, castrated VCaP tumors underwent tumor stasis and were significantly smaller compared to intact animals but increased PAP expression was noted after castration. In contrast, PSA and AR expression was reduced in castrated VCaP tumors compared to tumors from intact mice. DHT treatment of VCaP cells increased AR expression while decreasing both sPAP and TM-PAP at doses ranging from 10-7-10-14M for 24 h. CONCLUSIONS: Our findings demonstrate that PAP is expressed early in normal human fetal prostate development and may be a marker of the early stages of differentiation. DHT decreased the expression of both isoforms of PAP in vitro and castration increased PAP expression in vivo. TM-PAP may serve as a potential target for castration-resistant prostate cancer as its expression increases with castration.