Disabled-2 exerts its tumor suppressor activity by uncoupling c-Fos expression and MAP kinase activation

Disabled-2 (Dab2) is a putative tumor suppressor in breast and ovarian canc ers. Its expression is lost in a majority of tumors, and homozygous deletio ns have been identified in a small percentage of tumors. Dab2 expression is absent or very low in the majority of breast and ovarian cancer cell Lines , including MCF-7 and SK-Br-3 breast cancer cells. Transfection and express ion of Dab2 in MCF-7 and SK-Br-3 cells suppress tumorigenicity. The cells r each a much lower saturation density and have reduced ability to form colon ies on agar plates. In examining the signal transduction pathway of Dab2-tr ansfected cells, we found that serum-stimulated c-Fos expression was greatl y suppressed; however, the effects of Dab2 on MAPK family kinases were not as consistent. In MCF-2 and SK-Br-3 cells, although c-Fos expression was su ppressed, the Erk1/2, JNK, and p38(MAPK) activities were unchanged or even increased. Serum-stimulated c-Fos expression is dependent on MAPK/Erk activ ity because the MEK inhibitor PD98059 suppresses Erk activity and c-Fos exp ression. Therefore, Dab2 appears to uncouple MAPK activation and c-fos tran scription. Thus, me conclude that Dab2 re-expression suppresses tumorigenic ity by reducing c-Fos expression at a site downstream of the activation of MAPK family kinases. Because Dab2 is frequently lost in cancer; the uncoupl ing of MAPK activation and c-Fos expression may be a favored target for ina ctivation in tumorigenicity.