title: Activation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis.
abstract: The extracellular-regulated kinase (ERK) signaling pathway plays important roles in regulating the malignant potential of cancer cells in vitro. However, the effect of ERK signaling on the prognosis of human tumors is not clearly understood. The present study examined the expression of phosphorylated ERK1/2 (p-ERK1/2) as a hallmark of ERK activation, in relation to KRAS and BRAF mutations, in 63 endometrial cancer specimens with endometrioid-subtype, in order to clarify the prognostic value of p-ERK1/2 expression. Immmunohistochemical analysis revealed that 40 tumors (63%) expressed p-ERK1/2, with varying levels of expression. Total ERK1/2 expression was also evaluated in a subset of tumors; most cases expressed ERK1/2 constitutively but no correlation was observed with p-ERK expression, indicating that p-ERK1/2 staining was not due to ERK overexpression but to hyperactivation of ERK1/2. There was no statistically significant correlation between p-ERK1/2 expression and clinicopathological features, including patient age, International Federation of Gynecology and Obstetrics stage, pathological grade, myometrial invasion and lymph node metastasis. Sequencing analysis indicated that 23% of patients had a mutation in exon 1 of KRAS, whereas none of the patients had a mutation in exons 11 or 15 of BRAF, which are reportedly hot spots for mutation in many tumor types. There was no significant correlation between KRAS or BRAF status and p-ERK1/2 expression. Unexpectedly, patients with low p-ERK1/2 expression had significantly lower relapse-free survival (P = 0.041) and overall survival (P = 0.020). Multivariate Cox regression analysis indicated that p-ERK1/2 expression was an independent prognostic indicator for overall survival (P = 0.047). These findings suggest that ERK activation occurs in a KRAS- and BRAF-independent manner in endometrial cancer, and is associated with favorable prognosis.
authors: Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kanazawa University, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
authors: Yasunari
authors: Y
authors: Mizumoto
authors: Satoru
authors: S
authors: Kyo
authors: Noriko
authors: N
authors: Mori
authors: Junko
authors: J
authors: Sakaguchi
authors: Satoshi
authors: S
authors: Ohno
authors: Yoshiko
authors: Y
authors: Maida
authors: Manabu
authors: M
authors: Hashimoto
authors: Masahiro
authors: M
authors: Takakura
authors: Masaki
authors: M
authors: Inoue
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; C113580:U 0126; D004815:Epidermal Growth Factor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3