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The DUTT1 gene is located on human chromosome 3, band p12, within a region of nested homozygous deletions in breast and lung tumors. It is therefore a candidate tumor suppressor gene in humans and is the homologue (ROBO1) of the Drosophila axonal guidance receptor gene, Roundabout. We have shown previously that mice with a targeted homozygous deletion within the Dutt1/Robo1 gene generally die at birth due to incomplete lung development: survivors die within the first year of life with epithelial bronchial hyperplasia as a common feature. Because Dutt1/Robo1 heterozygous mice develop normally, we have determined their tumor susceptibility. Mice with a targeted deletion within one Dutt1/Robo1 allele spontaneously develop lymphomas and carcinomas in their second year of life with a 3-fold increase in incidence compared with controls: invasive lung adenocarcinomas are by far the predominant carcinoma. In addition to the mutant allele, loss of heterozygosity analysis indicates that these tumors retain the structurally normal allele but with substantial methylation of the gene's promoter. Substantial reduction of Dutt1/Robo1 protein expression in tumors is observed by Western blotting and immunohistochemistry. This suggests that Dutt1/Robo1 is a classic tumor suppressor gene requiring inactivation of both alleles to elicit tumorigenesis in these mice.

Original publication

DOI

10.1158/0008-5472.CAN-04-2561

Type

Journal article

Journal

Cancer Res

Publication Date

15/09/2004

Volume

64

Pages

6432 - 6437

Keywords

Adenocarcinoma, Alleles, Amino Acid Sequence, Animals, Base Sequence, Chromosomes, DNA Methylation, Gene Deletion, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Lung Neoplasms, Lymphoma, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Nerve Tissue Proteins, Promoter Regions, Genetic, Receptors, Immunologic, Tumor Suppressor Proteins