Abstract
High Stathmin expression has recently been associated with clinical progress in 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, clinicopathologic phenotype, and survival impact in endometrial cancer. A relationship with possible treatment targets was explored by integrated analysis of transcriptional alterations. Primary endometrial cancers from two independent patient series (n = 518/n = 286) were analyzed. Biomarkers were assessed by immunohistochemistry, FISH, flow cytometry, DNA oligonucleotide microarray, single-nucleotide polymorphism array, and Sanger sequencing, and related to clinicopathologic annotations and follow-up information. 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. On the basis of transcriptional differences between high/low pStathmin(S38) tumors, phosphoinositide 3-kinase (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). High pStathmin(S38) is a novel biomarker of increased tumor cell proliferation and impaired prognosis as reported here for independent cohorts of endometrial cancer and 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.
Highlights
Stathmin is a cytosolic phospho-protein known to be overexpressed in several malignancies [1]
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
On the basis of transcriptional differences between high/low pStathmin(S38) tumors, phosphoinositide 3-kinase (PI3K)/ mTOR/HSP90 were suggested as possible targets in pStathmin(S38)-high cases
Summary
Stathmin is a cytosolic phospho-protein known to be overexpressed in several malignancies [1]. It is suggested to be a marker of PTEN loss [2] and to play a role in tumor progression [1, 3]. It is considered important in signal transduction and involved in biologic processes such as cell-cycle progression, apoptosis, and cell migration [1]. Stathmin protein function is regulated at a posttranslational level by different mechanisms, of which phosphorylation is the most studied [1]. Stathmin has 4 Serine phospho-sites (Ser16, -25, -38, and -63), and phosphorylation is shown to inactivate Stathmin’s www.aacrjournals.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
