High Phospho-Stathmin(Serine38) expression identifies aggressive endometrial cancer and suggests an association with PI3Kinase inhibition
Menée sur deux cohortes indépendantes comportant respectivement 518 et 286 patientes atteintes d'un cancer primitif de l'endomètre, cette étude montre qu'un niveau d'expression tumorale élevé de la phospho-stathmine est associé à l'agressivité de la maladie
Purpose: High Stathmin expression is recently associated with clinical progress of endometrial cancers. Stathmin protein activity is modulated by phosphorylation, and the Serine38 site is one of four Stathmin phospho-sites. The presence and significance of pStathmin(S38) is largely unknown in human cancers, and we here examined the associations between this marker and tumor cell proliferation, clinico-pathologic phenotype and survival impact in endometrial cancer. A relationship with possible treatment targets were explored by integrated analysis of transcriptional alterations. Experimental Design: Primary endometrial cancers from two independent patient series (n=518/n=286) were analyzed. Biomarkers were assessed by IHC, FISH, flow cytometry, DNA oligonucleotide microarray, SNP array and Sanger sequencing, and related to clinico-pathologic annotations and follow-up information. Results: High pStathmin(S38) level was associated with poor prognosis, independent of other features, and correlated to increased tumor cell proliferation as well as high Stathmin levels. Based on transcriptional differences between high/low pStathmin(S38) tumors, PI3K/mTOR/HSP90 were suggested as possible targets in pStathmin(S38)-high cases. High pStathmin(S38) was associated with several PI3K pathway alterations: amplification of the 3q26 region, increased PIK3CA copy number (FISH) and a PI3K activation score (all p<0.05). Conclusions: High pStathmin(S38) is a novel biomarker of increased tumor cell proliferation and impaired prognosis as reported here for independent cohorts of endometrial cancer, not previously shown in human cancer. Our data support a rationale for further studies exploring effects of drugs inhibiting the PI3K signaling pathway in pStathmin(S38)-high endometrial cancer, including a potential value of pStathmin(S38) in predicting response to PI3K/mTOR/HSP90 inhibitors.
Clinical Cancer Research , résumé, 2013