Disabled-2 downregulation promotes epithelial-to-mesenchymal transition.
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 β (TGFβ) signalling loop, concomitant with increased expression of the TGFβ2 isoform.


CONCLUSIONS
Loss of Dab2 expression, commonly observed in breast cancer, may facilitate TGFβ-stimulated EMT, and therefore increase the propensity for metastasis.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
J C
JC
Martin
B-S
BS
Herbert
B A
BA
Hocevar
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D018631:ras Proteins