High phospho-Stathmin(Serine38) expression identifies aggressive endometrial cancer and suggests an association with PI3K inhibition
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High phospho-Stathmin(Serine38) expression identifies aggressive endometrial cancer and suggests an association with PI3K inhibition. / Wik, Elisabeth; Birkeland, Even; Trovik, Jone; Werner, Henrica M J; Hoivik, Erling A; Mjos, Siv; Krakstad, Camilla; Kusonmano, Kanthida; Mauland, Karen; Stefansson, Ingunn M; Holst, Frederik; Petersen, Kjell; Oyan, Anne M; Simon, Ronald; Kalland, Karl H; Ricketts, William; Akslen, Lars A; Salvesen, Helga B.
in: CLIN CANCER RES, Jahrgang 19, Nr. 9, 01.05.2013, S. 2331-41.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -