Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas.
ABSTRACT Mitogen-activated protein kinase (MAPK) plays a pivotal role in signal transduction. Activation of MAPK is regulated by upstream kinases including KRAS and BRAF, which are frequently mutated in low-grade ovarian serous carcinoma. This study evaluates the expression of active MAPK in ovarian serous carcinomas, with response to treatment and survival.
Expression of active MAPK was assessed by immunohistochemistry in 207 cases of ovarian serous tumors. Immunoreactivity was correlated with tumor grade, mutational status of KRAS and BRAF, in vitro drug resistance, and clinical outcome.
There was a lower frequency of expression of active MAPK in high-grade ovarian serous carcinomas as compared with low-grade serous tumors, including borderline tumors and low-grade serous carcinoma (P < 0.001). Active MAPK was present in all of the 19 low-grade tumors with either KRAS or BRAF mutations as well as in 14 (41%) of 34 tumors with wild-type KRAS and BRAF in both low- and high-grade carcinomas. Expression of active MAPK alone served as a good survival indicator in the 2-year follow-up (P = 0.037) but not in the 5-year follow-up (P = 0.145). However, a combination of expression of active MAPK and in vitro sensitivity of paclitaxel significantly correlated with a better prognosis in 5-year survival rate (P = 0.048) in patients with advanced-stage high-grade serous carcinoma.
Active MAPK is more frequently expressed in low-grade than in high-grade ovarian serous carcinoma. Active MAPK serves as a good prognostic marker in patients with high-grade serous carcinomas.
- SourceAvailable from: Jae Yong Han[Show abstract] [Hide abstract]
ABSTRACT: Activation of the mammalian target of rapamycin (mTOR) pathway enhances cell survival and growth by regulating the efficiency of protein translation. This study was conducted to evaluate the association of activated mTOR signaling molecules with the clinicopathologic characteristics in epithelial ovarian cancer. Immunohistochemical staining with antibodies against p-4EBP1, p-mTOR, and p-p70S6K were performed on specimens of 103 patients with ovarian cancer. Tumors were classified as chemoresistant in cases where time to recurrence after the end of chemotherapy was shorter than 6months. Expressions of p-mTOR, p-4EBP1, and p-p70S6K were detected in 47.6%, 85.4%, and 64.1% of all patients, respectively. p-4EBP1 overexpression was associated with advanced stage (p=0.04), histologic grade (p<0.01), residual mass (p<0.01), shorter disease-free survival rate (p=0.01) and chemoresistance (p=0.02). p-p70S6K was associated with residual mass with marginal significance (p=0.06). p-4EBP1 expression was correlated with p-p70S6K expression (r=0.42, p<0.01), whereas p-mTOR was not associated with expression of its downstream effectors or prognostic factors. Our findings suggest that p-4EBP1 expression was associated with poor prognostic factors of ovarian cancer and that p-4EBP1 overexpression may be a prognostic biomarker of ovarian cancer.Gynecologic Oncology 04/2011; 121(1):8-12. DOI:10.1016/j.ygyno.2010.12.364 · 3.69 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Ovarian serous carcinoma (OSC) is the most common and lethal histologic type of ovarian epithelial malignancy. Mutations of TP53 and dysfunction of the Brca1 and/or Brca2 tumor-suppressor proteins have been implicated in the molecular pathogenesis of a large fraction of OSCs, but frequent somatic mutations in other well-established tumor-suppressor genes have not been identified. Using a genome-wide screen of DNA copy number alterations in 36 primary OSCs, we identified two tumors with apparent homozygous deletions of the NF1 gene. Subsequently, 18 ovarian carcinoma-derived cell lines and 41 primary OSCs were evaluated for NF1 alterations. Markedly reduced or absent expression of Nf1 protein was observed in 6 of the 18 cell lines, and using the protein truncation test and sequencing of cDNA and genomic DNA, NF1 mutations resulting in deletion of exons and/or aberrant splicing of NF1 transcripts were detected in 5 of the 6 cell lines with loss of NF1 expression. Similarly, NF1 alterations including homozygous deletions and splicing mutations were identified in 9 (22%) of 41 primary OSCs. As expected, tumors and cell lines with NF1 defects lacked mutations in KRAS or BRAF but showed Ras pathway activation based on immunohistochemical detection of phosphorylated MAPK (primary tumors) or increased levels of GTP-bound Ras (cell lines). The TP53 tumor-suppressor gene was mutated in all OSCs with documented NF1 mutation, suggesting that the pathways regulated by these two tumor-suppressor proteins often cooperate in the development of ovarian carcinomas with serous differentiation.Neoplasia (New York, N.Y.) 01/2009; 10(12):1362-72, following 1372. DOI:10.1593/neo.08784 · 5.40 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: This study examined the status of KRAS and BRAF mutations, in relation to extracellular signal-regulated protein kinase (ERK) activation in 58 ovarian carcinomas to clarify the clinicopathological and prognostic significance of KRAS/BRAF mutations. Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. The frequency of KRAS/BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than that in the other histological type (32.3% : 10/31). Phosphorylated ERK1/2 (p-ERK1/2) expression was identified in 18 (38.2%) out of 45 ovarian carcinomas. KRAS/BRAF mutation was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage I, II (P<0.001), and p-ERK1/2 (P<0.001). No significant correlations between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival were found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy (P=0.2460, P=0.9339, respectively). Next, to clarify the roles of ERK1/2 activation in ovarian cancers harbouring KRAS or BRAF mutations, we inactivated ERK1/2 in ovarian cancer cells using CI-1040. Cl-1040 is a compound that selectively inhibits MAP kinase kinase (MEK), an upstream regulator of ERK1/2, and thus prevents ERK1/2 activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated cancer cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. This was evident in both in vitro and in vivo studies. The findings in this study indicate that an activated ERK1/2 pathway is critical to tumour growth and survival of ovarian cancers with KRAS or BRAF mutations. Furthermore, they suggest that the CI-1040-induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian cancers. Therefore, ovarian cancer patients with KRAS or BRAF mutations may benefit from CI-1040 treatment.British Journal of Cancer 11/2008; 99(12):2020-8. DOI:10.1038/sj.bjc.6604783 · 4.82 Impact Factor