Distribution of HER‐2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma

Høgdall, Estrid; Christensen, Lise; Kjær, Susanne K.; Blaakær, Jan; Bock, Johannes E.; Glud, Eva; Nørgaard‐Pedersen, Bent; Høgdall, Claus

doi:10.1002/cncr.11476

Cited by 125 publications

(91 citation statements)

References 30 publications

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“…In other studies, the percentage of c-erb-B2-positive tumors ranged from 15% to 30%. 12,21,22 It is noteworthy that c-erb-B2 overexpression in our series was observed only in carcinomas: mostly in highgrade carcinomas. Surprisingly, despite this correlation with aggressive morphology, results of the survival study did not indicate statistical significance.…”

Section: Discussionmentioning

confidence: 55%

“…Surprisingly, despite this correlation with aggressive morphology, results of the survival study did not indicate statistical significance. Although the predictive value of c-erb-B2 in ovarian carcinomas is not clear, some studies have shown a significantly worse prognosis for patients with positive tumors, 11,12,21 whereas others did not observe this correlation. [23][24][25] Similarly, EGFR reportedly was overexpressed in 30% to 77% of ovarian carcinomas, and its association with a poor prognosis, like in our series, was not verified.…”

Section: Discussionmentioning

confidence: 96%

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Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Castellví

García

Rojo

et al. 2006

Cancer

163

114

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BACKGROUND.Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream.METHODS.One hundred twenty‐nine ovarian epithelial tumors were studied, including 20 serous cystadenomas, 7 mucinous cystadenomas, 11 serous borderline tumors, 16 mucinous borderline tumors, 29 serous carcinomas, 16 endometrioid carcinomas, 15 clear cell carcinomas, and 15 mucinous carcinomas. Tissue microarrays were constructed, and immunohistochemistry for the receptors epidermal growth factor receptor (EGFR) and c‐erb‐B2 was performed and with phosphorylated antibodies for protein kinase B (AKT), 4EBP1, p70S6K, S6, and ERK.RESULTS.Among 129 ovarian neoplasms, 17.8% were positive for c‐erb‐B2, 9.3% were positive for EGFR, 47.3% were positive for phosphorylated AKT (p‐AKT), 58.9% were positive for p‐ERK, 41.1% were positive for p‐4EBP1, 26.4% were positive for p70S6K, and 15.5% were positive for p‐S6. Although EGFR, p‐AKT, and p‐ERK expression did not differ between benign, borderline, or malignant tumors, c‐erb‐B2, p‐4EBP1, p‐p70S6K, and p‐S6 were expressed significantly more often in malignant tumors. Only p‐4EBP1 expression demonstrated prognostic significance (P = .005), and only surgical stage and p‐4EBP1 expression had statistical significance in the multivariate analysis.CONCLUSIONS.In patients with ovarian carcinoma, significant expression of p‐4EBP1 was associated with high‐grade tumors and a poor prognosis, regardless other oncogenic alterations upstream. This finding supports the study of this factor as a hallmark or pivotal factor in cell signaling in ovarian carcinoma that may crucial in the transmission of the proliferation cell signal and may reflect the real oncogenic role of this pathway in ovarian tumors. Cancer 2006. © 2006 American Cancer Society.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 96%

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Castellví

García

Rojo

et al. 2006

Cancer

163

114

View full text Add to dashboard Cite

show abstract

“…In fact, the ErbB-2 antibody treatment Herceptin is clinically effective in treating a subset of breast cancer patients (21). Overexpression of ErbB-2 also correlates with poor outcome in ovarian cancer (41,42), although antibody therapy for ErbB-2 is not used clinically for the treatment of ovarian cancer. ErbB-2 is expressed in OSE cells (43) in approximately 25% to 30% of ovarian cancer (41,44,45) and in cultured ovarian cancer cells, including SKOV3 cells.…”

Section: Discussionmentioning

confidence: 99%

Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells

Warrenfeltz

Lott

Palmer

et al. 2008

Molecular Cancer Research

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The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein -coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2 -overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time-and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A -mediated, protein kinase C -mediated, epidermal growth factor receptor -mediated, and ErbB-2 -mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype.

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“…For OC, 20-30% of primary stage III/IV tumours show ERBB2 overexpression (Hellstrom et al, 2001). Protein expression using antibody staining on a subset of ovarian tumours from the MALOVA study showed that 39% of the carcinomas overexpressed ERBB2 (Hogdall et al, 2003b).…”

mentioning

confidence: 99%

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

et al. 2009

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Low -moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in B1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P dominant ¼ 0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case -control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80 -0.99) and remained statistically significant (P dominant ¼ 0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P global ¼ 0.034) and a haplotype in BRAF that had a protective effect (P global ¼ 0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

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Distribution of HER‐2 overexpression in ovarian carcinoma tissue and its prognostic value in patients with ovarian carcinoma

Cited by 125 publications

References 30 publications

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Phosphorylated 4E binding protein 1: A hallmark of cell signaling that correlates with survival in ovarian cancer

Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

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