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Deciphering the oncogenic role of CUX1 through the study of mouse models

Authors
Publisher
McGill University
Publication Date
Keywords
  • Biology - Molecular
Disciplines
  • Biology
  • Medicine

Abstract

There is increasing evidence that CUX1 can act as an oncogene in various cell types. First of all, it was found to be overexpressed in different human tumors, such as in uterine leiomyomas, breast tumors and pancreatic tumors. Both p75 and p110 were also found to be overexpressed in tumor cell lines of different origins. My research project has focused on characterizing the oncogenic potential of short CUX1 isoforms through the study of transgenic mice. The first model we used was to overexpress p75 CUX1 under the control of the cytomegalovirus enhancer-chicken β-actin promoter. Interestingly, these mice developed polycystic kidneys at variable penetrance and severity, correlating with transgene expression levels. Cystic kidneys were found to display enhanced proliferation and also showed an upregulation of c-myc and downregulation of p27KIP1. The second model we used was to overexpress p75 or p110 CUX1 under the control of the mouse mammary tumor virus-long terminal repeat in the hypoxanthine phosphorybosyltransferase locus. The first phenotype we observed was that p75 CUX1 transgenic virgin female mice of the first backcross generations developed a myeloproliferative-disease-like myeloid leukemia. These results indicate that overexpression of p75 CUX1 can alter the proliferation and differentiation of some hematopoietic cells. The second phenotype we observed in these mice was that both p75 CUX1 and p110 CUX1 mice of pure FVB background developed mammary tumors of various histopathologies. Metastasis to the lung was observed in the p75 CUX1 transgenic mice only. Comparisons between tumors and adjacent normal mammary glands revealed that transgenes were overexpressed in most but not all tumors, yet in all cases tested CUX1 DNA binding was increased. Interestingly, higher expression of erbB2 mRNA was seen in most solid carcinomas, while adenosquamous carcinomas displayed higher expression of various Wnt

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