Characterization of Active Mitogen-Activated Protein Kinase in Ovarian Serous Carcinomas

Hsu, Chih‐Yi; Bristow, Robert E.; Seok, Moon; Wang, Brant G.; Ho, Chung-Liang; Kurman, Robert J.; Wang, Tian‐Li; Shih, Ie‐Ming

doi:10.1158/1078-0432.ccr-04-0893

Cited by 126 publications

(99 citation statements)

References 16 publications

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“…21 We demonstrated that 92% of PSTTs expressed high levels of activated MAPK (2ϩ and 3ϩ) ( Table 1). The immunoreactivity was diffuse in PSTT and it was predominantly located in the cytoplasm.…”

Section: Expression Of Active Mapk In Normal Trophoblast and Psttsmentioning

confidence: 82%

“…The antibody used was a rabbit polyclonal antibody, pTEpY that specifically reacted with the active (phosphorylated) but not the unphosphorylated MAPK (Promega, Madison, WI), 21 and an anti-ERK1/2 polyclonal antibody that reacted with total MAPK (Promega). The specificity of pTEpY in immunohistochemistry was previously reported.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…The specificity of pTEpY in immunohistochemistry was previously reported. [21][22][23] Immunohistochemistry was performed on tissue sections at a dilution of 1:500 followed by the EnVisionϩSystem using the peroxidase method (DAKO, Carpinteria, CA). The percentage of positive cells was estimated by randomly counting ϳ500 tumor cells from three different high-power fields (ϫ40) within one specimen.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Activation of Mitogen-Activated Protein Kinase Is Required for Migration and Invasion of Placental Site Trophoblastic Tumor

Köbel

Pohl

Hauptmann

et al. 2005

The American Journal of Pathology

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Section: Expression Of Active Mapk In Normal Trophoblast and Psttsmentioning

confidence: 82%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

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Activation of Mitogen-Activated Protein Kinase Is Required for Migration and Invasion of Placental Site Trophoblastic Tumor

Köbel

Pohl

Hauptmann

et al. 2005

The American Journal of Pathology

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“…Their results, along with the frequency and location of cancer-associated ERBB2 mutations, strongly suggest that this domain is critical for the regulation (enhancement) of ERBB2 activity. In the case of ovarian serous LMP tumors, activation of the RAS-MAPK pathway is evident not only through activation of mutant RAS, BRAF, and ERBB2 but also in downstream activity of (phosphorylated) ERK (75).…”

Section: Discussionmentioning

confidence: 99%

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Anglesio

Arnold²,

George³

et al. 2008

Molecular Cancer Research

111

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Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in >70% of cases compared with f12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2

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“…5,19 -21 Expression of active MAPK was more frequently observed in low-grade serous tumors than in high-grade ovarian serous carcinomas that have rare mutations in either BRAF or KRAS. 22 Moreover, BRAF and KRAS mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer. 11,23 Interestingly, BRAF or KRAS mutations can be detected in morphologically normal-appearing cyst epithelium that is adjacent to a serous borderline tumor but not in the cystadenomas without concurrent borderline tumors, suggesting the mutations may occur early during tumor progression of ovarian low-grade serous tumors.…”

mentioning

confidence: 99%

Mutant BRAF Induces DNA Strand Breaks, Activates DNA Damage Response Pathway, and Up-Regulates Glucose Transporter-1 in Nontransformed Epithelial Cells

Sheu

Guan

Tsai

et al. 2012

The American Journal of Pathology

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Although the oncogenic functions of activating BRAF mutations have been clearly demonstrated in human cancer, their roles in nontransformed epithelial cells remain largely unclear. Investigating the cellular response to the expression of mutant BRAF in nontransformed epithelial cells is fundamental to the understanding of the roles of BRAF in cancer pathogenesis. In this study, we used two nontransformed cyst108 and RK3E epithelial cell lines as models in which to compare the phenotypes of cells expressing BRAF WT and BRAF V600E . We found that transfection of the BRAF V600E , but not the BRAF WT , expression vector suppressed cellular proliferation and induced apoptosis in both cell types. BRAF V600E generated reactive oxygen species, induced DNA double-strand breaks, and caused subsequent DNA damage response as evidenced by an increased number of pCHK2 and ␥H2AX nuclear foci as well as the up-regulation of pCHK2, p53, and p21. Because BRAF and KRAS (alias Ki-ras) mutations have been correlated with GLUT1 up-regulation, which encodes glucose transporter-1, we demonstrated here that expression of BRAF V600E , but not BRAF WT , was sufficient to up-regulate GLUT1. Taken together, our findings provide new insights into mutant BRAF-induced oncogenic stress that is manifested by DNA damage and growth arrest by activating the pCHK2-p53-p21 pathway in nontransformed cells, while it also confers tumor-promoting phenotypes such as the up-regulation of GLUT1 that contributes to enhanced glucose metabolism that characterizes tumor cells.

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Characterization of Active Mitogen-Activated Protein Kinase in Ovarian Serous Carcinomas

Abstract: Conclusions: 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.

Cited by 126 publications

References 16 publications

Activation of Mitogen-Activated Protein Kinase Is Required for Migration and Invasion of Placental Site Trophoblastic Tumor

Activation of Mitogen-Activated Protein Kinase Is Required for Migration and Invasion of Placental Site Trophoblastic Tumor

Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors

Mutant BRAF Induces DNA Strand Breaks, Activates DNA Damage Response Pathway, and Up-Regulates Glucose Transporter-1 in Nontransformed Epithelial Cells

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