Notch3Gene Amplification in Ovarian Cancer

Abstract

Gene amplification is one of the common mechanisms that activate oncogenes. In this study, we used single nucleotide polymorphism array to analyze genome-wide DNA copy number alterations in 31 high-grade ovarian serous carcinomas, the most lethal gynecologic neoplastic disease in women. We identified an amplicon at 19p13.12 in 6 of 31 (19.5%) ovarian high-grade serous carcinomas. This amplification was validated by digital karyotyping, quantitative real-time PCR, and dual-color fluorescence in situ hybridization (FISH) analysis. Comprehensive mRNA expression analysis of all 34 genes within the minimal amplicon identified Notch3 as the gene that showed most significant overexpression in amplified tumors compared with nonamplified tumors. Furthermore, Notch3 DNA copy number is positively correlated with Notch3 protein expression based on parallel immunohistochemistry and FISH studies in 111 high-grade tumors. Inactivation of Notch3 by both γ-secretase inhibitor and Notch3-specific small interfering RNA suppressed cell proliferation and induced apoptosis in the cell lines that overexpressed Notch3 but not in those with minimal amount of Notch3 expression. These results indicate that Notch3 is required for proliferation and survival of Notch3-amplified tumors and inactivation of Notch3 can be a potential therapeutic approach for ovarian carcinomas. (Cancer Res 2006; 66(12): 6312-8)

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

“…Some studies have suggested that in some cancers increased Notch gene copy number can correlate with increased Notch signaling (Bray, 2006;Leong and Karsan, 2006;Park et al, 2006). In our study, although we noted that the Notch 2 locus (1p13-11) in Mary-X was moderately amplified on array comparative genomic hybridization, the Notch 3 locus was not amplified.…”

“…The therapeutic efficacy of notch inhibitors has been observed in other human cancer cell lines (Haruki et al, 2005;Park et al, 2006). Although pharmacological therapy with GSI-I was very effective in vitro, it was less effective in vivo, probably because of diffusion-limited effects of either tissue solubility or half-life.…”

Amplicon profiles in ovarian serous carcinomas

“…6,30 Notch3 amplicon has been recently reported in ovarian serous carcinomas based on fine mapping of the chr19p13.12 amplicon from high-grade serous carcinomas using a part of the SNP array results reported here. 16 HBXAP/Rsf-1 functions as a chromatin remodeling protein by partnering with hNSF2H. The resulting complex plays an important role in a variety of cellular functions.…”

“…SNP array was used because it has been recently demonstrated to be feasible and robust and, most important, this technology provides high resolution which facilitates detection of DNA copy number changes. [14][15][16] In this study, we focused on amplified regions because it appeared more feasible to validate amplicons rather than deletions in regions in which the DNA copy number changes were usually subtle (from 2 to 1 or 0 copy). Our results demonstrate that CCNE1, Notch3, HBXAP/Rsf-1, AKT2 and PIK3CA are among the most frequently amplified loci in high-grade serous carcinomas.…”

High-Resolution Mapping of Structural Mutations in Prostate Cancer with Single Nucleotide Polymorphism Arrays

“…For instance, MITF was shown to be an oncogene after amplifications were observed at this locus in an SNP array study of the NCI60 panel of cancer cell lines [39 ]. More recently, amplifications of NOTCH3 were noted in ovarian tumors by an SNP array analysis, and the functional role of NOTCH3 was suggested by the ability to suppress cell proliferation by inhibiting NOTCH3 [40 ].…”