Dopamine and cAMP-regulated phosphoprotein 32kDa (DARPP-32), protein phosphatase-1 and cyclin-dependent kinase 5 expression in ovarian cancer.

ABSTRACT

Dopamine and cyclic-AMP activated phosphoprotein Mr32kDa (DARPP-32) is a central signalling protein in neurotransmission. Following DARPP-32 phosphorylation by protein kinase A (PKA), DARPP-32 becomes a potent protein phosphatase 1 (PP1) inhibitor. DARPP-32 can itself inhibit PKA following DARPP-32 phosphorylation by cyclin-dependent kinase 5 (Cdk5). Increasing evidence indicates a role for DARPP-32 and its associated signalling pathways in cancer; however, its role in ovarian cancer remains unclear. Using immunohistochemistry, expression of DARPP-32, PP1 and Cdk5 was determined in a large cohort of primary tumours from ovarian cancer patients (n = 428, 445 and 434 respectively) to evaluate associations between clinical outcome and clinicopathological criteria. Low cytoplasmic and nuclear DARPP-32 expression was associated with shorter patient overall survival and progression-free survival (P = .001, .001, .004 and .037 respectively). Low nuclear and cytoplasmic DARPP-32 expression remained significantly associated with overall survival in multivariate Cox regression (P = .045, hazard ratio (HR) = 0.734, 95% confidence interval (CI) = 0.542-0.993 and P = .001, HR = 0.494, 95% CI = 0.325-0.749, respectively). High cytoplasmic and nuclear PP1 expression was associated with shorter patient overall survival and high cytoplasmic PP1 expression with shorter progression-free survival (P = .005, .033, and .037, respectively). High Cdk5 expression was associated with shorter progression-free survival (P = .006). These data suggest a role for DARPP-32 and associated signalling kinases as prognostic markers with clinical utility in ovarian cancer.