MP37-20 NEOADJUVANT ANDROGEN DEPRIVATION THERAPY INDUCES SENESCENCE IN RADICAL PROSTATECTOMY SPECIMENS

Abstract

INTRODUCTION AND OBJECTIVES: Better biomarkers are needed in prostate cancer (PCa) to predict disease recurrence and guide optimal therapy. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and clinical outcomes in localized disease. METHODS: Radical prostatectomy (RP) specimens (þ/disease recurrence) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Univariable and multivariable associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts and in-silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa proliferation, invasion and tumor growth. RESULTS: Four candidate genes were differentially expressed in PCa recurrence, and of these, low AXIN2 expression was internally validated. In external cohorts and in silico, low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. In vitro and in vivo, low AXIN2 expression was associated with a cancer stem-like cell-surface signature, and siRNA knockdown of AXIN2 resulted in significantly greater invasiveness. Conversely, ectopic overexpression of AXIN2 significantly reduced cell proliferation and tumor growth in mice (Figure). CONCLUSIONS: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation and tumor growth. Based on these novel roles in PCa, AXIN2 may represent a new putative biomarker and potential therapeutic target in this disease.