High phospho-Stathmin(Serine38) expression identifies aggressive endometrial cancer and suggests an association with PI3K inhibition

TY - JOUR

T1 - High phospho-Stathmin(Serine38) expression identifies aggressive endometrial cancer and suggests an association with PI3K inhibition

AU - Wik, Elisabeth

AU - Birkeland, Even

AU - Trovik, Jone

AU - Werner, Henrica M J

AU - Hoivik, Erling A

AU - Mjos, Siv

AU - Krakstad, Camilla

AU - Kusonmano, Kanthida

AU - Mauland, Karen

AU - Stefansson, Ingunn M

AU - Holst, Frederik

AU - Petersen, Kjell

AU - Oyan, Anne M

AU - Simon, Ronald

AU - Kalland, Karl H

AU - Ricketts, William

AU - Akslen, Lars A

AU - Salvesen, Helga B

N1 - ©2013 AACR.

PY - 2013/5/1

Y1 - 2013/5/1

N2 - PURPOSE: 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.EXPERIMENTAL DESIGN: 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.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. 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).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 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.

AB - PURPOSE: 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.EXPERIMENTAL DESIGN: 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.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. 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).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 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.

KW - Antineoplastic Agents

KW - Carcinoma

KW - Cell Proliferation

KW - Chromosomes, Human, Pair 3

KW - Endometrial Neoplasms

KW - Female

KW - Gene Amplification

KW - Humans

KW - Kaplan-Meier Estimate

KW - Oligonucleotide Array Sequence Analysis

KW - Phenotype

KW - Phosphatidylinositol 3-Kinases

KW - Phosphoproteins

KW - Phosphorylation

KW - Prognosis

KW - Proportional Hazards Models

KW - Protein Processing, Post-Translational

KW - Stathmin

KW - TOR Serine-Threonine Kinases

KW - Transcriptome

KW - Tumor Markers, Biological

U2 - 10.1158/1078-0432.CCR-12-3413

DO - 10.1158/1078-0432.CCR-12-3413

M3 - SCORING: Journal article

C2 - 23538402

VL - 19

SP - 2331

EP - 2341

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 9

ER -