title: Concomitant activation of AKT with extracellular-regulated kinase 1/2 occurs independently of PTEN or PIK3CA mutations in endometrial cancer and may be associated with favorable prognosiss.
abstract: Deregulated signaling via the phosphatidylinositol 3-kinase (PI3K) pathway is common in many types of cancer, but its clinicopathological significance in endometrial cancer remains unclear. In the present study, we examined the status of the PI3K signaling pathway, especially in relation to PTEN and PIK3CA status, in endometrioid-type endometrial cancer. The immunohistochemical analysis revealed a high level of phosphorylated (p)-AKT expression, which is a hallmark of activated PI3K signaling, in approximately 60% of endometrial cancers. There was no correlation between p-AKT expression and clinicopathological characteristics, such as International Federation of Gynecology and Obstetrics stage, tumor grade, and myometrial invasion. Unexpectedly, a high level of p-AKT expression occurred independently of the presence of PTEN or PIK3CA mutations. Furthermore, p-AKT expression did not correlate with the expression of potential downstream targets, including p-mTOR and p-FOXO1/3a. In turn, p-AKT expression was strongly associated with extracellular-regulated kinase 1/2 expression (P = 0.0031), which is representative of the activated RAS-MAP kinase pathway. Kaplan-Meier analysis suggested that low p-AKT expression was associated with low rates of relapse-free survival, although the difference was not statistically significant, indicating that AKT activation does not confer worse prognosis. The present study demonstrates the presence of complex signaling pathways that might mask the conventional tumorigenic PTEN-PI3K-AKT-mTOR pathway, and strongly suggests a close association between the extracellular-regulated kinase and PI3K pathways in this tumor type.
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Mori
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
authors.forename: Junko
authors.initials: J
authors.lastname: Sakaguchi
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Mizumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohno
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Maida
authors.forename: Manabu
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takakura
authors.forename: Masaki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000601:surgery; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human