Schematic summarizing the role of signaling Smads in epithelial carcinogenesis. Smad2 loss in epithelia upregulates Snail and HGF expression through increasing Smad4 to the SBE of target genes recruited by Smad3. Upregulation of Snail and HGF resulted in epithelial cells undergoing EMT and increasing stromal angiogenesis respectively, which accelerates chemically induced SCC formation. Smad4 deletion in epithelia downregulates Fanc/Brca genes, inactivates PTEN and p21, and increases TGFβ expression. Reduction in Fanc/Brca pathway genes caused DNA damage and is an initiating factor for tumorigenesis. Inactivation of PTEN and p21 increase cell proliferation and inhibit cell apoptosis, cooperating with TGFβ-induced inflammation to promote SCC development and progression. Smad3 loss in skin inhibits TGFβ induced inflammation and exhibits resistance to chemical induced skin carcinogenesis.