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Identification of novel oncogenes collaborating with Erbb2 by Insertional Mutagenesis

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Identification of novel oncogenes collaborating with Erbb2 by Insertional Mutagenesis

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Samenvatting

Cancer is one of the most important causes of death in the world, while breast cancer has the highest mortality rate among women. A large part of breast cancer research is devoted to understanding the genetic basis of breast cancer. There are several known oncogenes involved in human breast carcinogenesis, but it is likely that many more oncogenes are involved in breast cancer. To discover these novel oncogenes, a Mouse Mammary Tumor Virus (MMTV) mediated insertion mutagenesis screen has been performed in an MMTV-Erbb2 transgenic mouse model, for ERBB2 positive breast cancer. A total of 112 tumors of the MMTV-Erbb2 model were screened using the MMTV Splinkerette PCR to localize proviral MMTV proviral insertions. In this screen we mapped fourteen Common Insertion Sites. Six of these were associated with genes not previously involved in mammary tumorigenesis, including Eras, Dnahc1, Gpc6, Irs4, Ptchd3 and Sep15.
Erbb2 and Eras expression was examined in 65 MMTV-Erbb2 tumors the by RT-PCR experiments. Four tumors from the Erbb2 transgenic mice showed no overexpression of Erbb2, but tagging of oncogenic Wnt genes. Further analysis revealed a significant inverse correlation between Erbb2 expression and Wnt tagging (p=0,013; X2 test), suggesting that Wnt genes take over the primary oncogenic event in the tumors with no Erbb2 overexpression. MMTV proviral insertions mapped in the Eras locus, and the orientation of the virus suggested that Eras is the retroviral target. Indeed proviral MMTV in the Eras locus significantly correlated with Eras mRNA expression (p=0,027; X2 test), validating that Eras is the MMTV target. Eras was overexpressed in nine (14%) Erbb2 positive tumors, and only in four (10%) Wild Type BALB/c tumors and one (4%) Wild Type FVB tumor. Between the two Wild Type mice strains there no significant difference in Eras expression (p=0,336; X2 test), and is no significant difference in expression frequency of Eras between the transgenic Erbb2 and WT BALB/c mice (p=0,636; X2 test) and the transgenic Erbb2 and WT FVB mice (p=0,179; X2 test). This means that Eras does not specifically collaborate with Erbb2 in tumor formation.
The relevance of ERAS for human breast cancer has also been investigated. Two breast cancer cell lines (15%) showed expression of ERAS, and four cell lines showed low expression of ERAS, indicating that ERAS may play a role in human breast carcinogenesis.

Toon meer
OrganisatieHogeschool Utrecht
OpleidingBiologie en Medisch Laboratorium Onderzoek
AfdelingLife Sciences en Chemistry
PartnerNetherlands Cancer Institute
Jaar2008
TypeBachelor
TaalEngels

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