PO-433 Prognostic relevance of PP1 in breast cancer

Abstract

IntroductionProtein phosphatase 1 (PP1) is one of the major cellular serine/threonine protein phosphatases and it is implicated in the regulation of many cellular events including glycogen metabolism, neuronal signalling and protein synthesis. In addition, PP1 indirectly controls cell cycle progression by modulating the phosphorylation status of key cell-regulatory proteins, including retinoblastoma protein (pRb). In mammalian cells, three genes encode four isoforms of PP1 designated as PP1α, PP1β, PP1γ1 and PP1γ2. These isoforms are expressed in all tissues and cellular compartments except PP1γ2, which is found only in testes.Despite the numerous functions in which it is involved, PP1 itself does not exhibit substrate specificity. Indeed, specificity is achieved by its interaction with ~200 different regulatory proteins that associate with PP1 to form highly specific holoenzymes. These regulatory subunits bind to the catalytic subunit of PP1 (PP1C) generating structures and specific functions. Three different PP1C isoforms have been described, PPP1CA, PPP1CB and PPP1CC.As the role of PP1 in cell cycle regulation is crucial and its specificity depends on the binding of the regulatory protein to PP1C, we investigated the prognostic relevance of the different PP1 catalytic subunits in human tumours.Material and methodsTo evaluate the prognostic relevance of the three PP1 catalytic subunits in human tumours, we analysed correlations between grade, patient survival, tumour recurrence and PPP1CA/B/C gene expression in independent patient cohorts. To this end, we used different public transcriptomic databases of breast cancer from Oncomine (Compendia Biosciences, www.oncomine.org) and from R2: Genomics analysis and visualisation platform (http://r2.amc.nl/).Results and discussionsThe downregulation of two of the three catalytic subunits of PP1 (PPP1CA and C) is associated with worse prognosis in breast tumours, correlating with worse overall survival, a higher tumour grade and ER positive status.ConclusionThe catalytic subunit of PP1 seems to have a prognostic and predictive value for breast cancer. As several PP1 regulatory proteins have been described, identifying and understanding their role in PP1 regulation during cell cycle progression might be important to control cell growth. Therefore, PP1 regulatory proteins might be interesting as new therapeutic targets and/or biomarkers in cancer.