Defects in transforming growth factor-beta signaling cooperate with a Ras oncogene to cause vapid aneuploidy and malignant transformation of mouse keratinocytes

Genetic inactivation of the transforming growth factor-beta (TGF-beta) sign aling pathway can accelerate tumor progression in the mouse epidermal model of multistage carcinogenesis. By using an in vitro model of keratinocyte t ransformation that parallels in vivo malignant conversion to squamous cell carcinoma, we show that v-ras(Ha) transduced primary TGF-beta 1-/- keratino cytes and keratinocytes expressing a TGF-beta type II dominant-negative rec eptor transgene have significantly higher frequencies of spontaneous transf ormation than control genotypes, Malignant transformation in the TGF-beta 1 -/- keratinocytes is preceded by aneuploidy and accumulation of chromosomal aberrations. Similarly, transient inactivation of TGF-beta signaling with a type II dominant-negative receptor adenovirus causes rapid changes in plo idy, Exogenous TGF-beta 1 can suppress aneuploidy, chromosome breaks, and m alignant transformation of the TGF-beta 1-/- keratinocytes at concentration s that do not significantly arrest cell proliferation. These results point to genomic instability as a mechanism by which defects in TGF-beta signalin g could accelerate tumor progression in mouse multistage carcinogenesis.