Open AccessActivation of ERK1/2 occurs independently of KRAS or BRAF status in endometrial cancer and is associated with favorable prognosis
Author(s) -
Mizumoto Yasunari,
Kyo Satoru,
Mori Noriko,
Sakaguchi Junko,
Ohno Satoshi,
Maida Yoshiko,
Hashimoto Manabu,
Takakura Masahiro,
Inoue Masaki
Publication year - 2007
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2007.00445.x
Subject(s) - kras , mapk/erk pathway , endometrial cancer , cancer research , kinase , cancer , exon , dusp6 , medicine , biology , oncology , gene , phosphorylation , colorectal cancer , genetics , phosphatase , protein phosphatase 2
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. ( Cancer Sci 2007; 98: 652–658)