1601

DAB2

Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila);DAB2;Dab, mitogen-responsive phosphoprotein, homolog 2 (Drosophila)

adaptor molecule disabled-2|differentially expressed in ovarian carcinoma 2|differentially-expressed protein 2|disabled homolog 2|disabled homolog 2, mitogen-responsive phosphoprotein

5p13.1

protein-coding

BACKGROUND: metastatic tumour cells are characterised by acquisition of migratory and invasive properties; properties shared by cells, which have undergone epithelial-to-mesenchymal transition (EMT). Disabled-2 (Dab2) is a putative tumour suppressor whose expression has been shown to be downregulated in various cancer types including breast cancer; however, its exact function in suppressing tumour initiation or progression is unclear. METHODS: Disabled-2 isoform expression was determined by RT-PCR analysis in human normal and breast tumour samples. Using shRNA-mediated technology, Dab2 was stably downregulated in two cell model systems representing nontumourigenic human mammary epithelial cells. These cells were characterised for expression of EMT markers by RT-PCR and western blot analysis. RESULTS: Decreased expression of the p96 and p67 isoforms of Dab2 is observed in human breast tumour samples in comparison to normal human breast tissue. Decreased Dab2 expression in normal mammary epithelial cells leads to the appearance of a constitutive EMT phenotype. Disabled-2 downregulation leads to increased Ras/MAPK signalling, which facilitates the establishment of an autocrine transforming growth factor beta (TGFbeta) signalling loop, concomitant with increased expression of the TGFbeta2 isoform. CONCLUSION: Loss of Dab2 expression, commonly observed in breast cancer, may facilitate TGFbeta-stimulated EMT, and therefore increase the propensity for metastasis.