Low Darpp32 And Related Profiles In Glioblastomas

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC DARPP32 (PPP1R1B, an inhibitor of protein phosphatase-1) plays a central role in dopamine signalling in the brain and has been associated with a number of diverse conditions, ranging from nicotine dependence to cancer drug resistance, while its overexpression has been reported as pro-oncogenic in various epithelial cancers. Since data on this molecule in astrocytic carcinogenesis are missing, this study focused on DARPP32 expression and related profiles in astrocytic gliomas. In a panel of 157 routinely diagnosed astrocytic glioma tissues we assessed (i) relative expression of DARPP32 along with 21 additional transcript targets from key regulators in signalling pathways commonly disturbed in glioblastomas (GBM), (ii) genomic status of selected genes and (iii) activation status of the Akt and Stat pathways. Normal brain tissues expressed DARPP32 at considerable levels. In comparison, the expression of this molecule was strongly decreased (low = decrease of >1 order of magnitude) according to histological grade, more frequently in grade IV (GBM, 89/116 [77%]) than in grade III (11/22 [50%]) and grade II (4/19 [21%]) tumors (p<0.0001). Low DARPP32 was associated with EGFR gene amplification (p=0.0006) and mRNA/protein overexpression; high pro-angiogenic VEGF isoform (p=0.0002) and hTERT expression (p=0.0008); low SRC/STAT expression (STAT3, 5A and 5B p's<0.0001) but common Stat3 (p=0.0003) and Akt/PKB phosphorylation (p=0.0036). Two specific Akt deactivating phosphatases, PHLPP2 and PHLPP1 were also identified to be downregulated/absent in GBM (63% and 23%, respectively), in line with their proposed tumor suppressor role. Strikingly, low expression of these two genes almost coincided with low DARPP32, with strongly decreased DARPP32/PHLPP2 and DARPP32/PHLPP2/PHLPP1 in 54% and 17.2% of GBMs, respectively. In 66 out of the 116 GBM patients with known follow-up, this latter profile was associated with a slightly better survival (log rank, p=0.0496); all corresponding tumors had activated Akt-Thr308 but lacked EGFR/EGFRvIII, MET, SRC, STATs, TERT (12/12), and VEGF isoform (8/12) overexpression, and 12q gene amplification (10/12). In conclusion, DARPP32 expression is strongly decreased in high grade astrocytic tumors where, in contrast to what has been described for common epithelial cancers, low DARPP32 seems to be related to pro-oncogenic and adverse prognostic parameters. This study also demonstrates that, except for PTEN, additional phosphatases regulating Akt signalling are commonly missing in GBM, mostly in parallel with low DARPP32. Further dissecting the molecular environment accompanying the decreased expression of these genes seems important for understanding the behaviour of this highly heterogeneous group of tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 791.