Abstract Identifying the physiologic relevance of cancer-associated genetic polymorphisms is a major challenge. Several changes in the coding sequence of β integrin subunits have now been described in human tumors. One of these, T188Iβ1, was identified as a heterozygous mutation in a poorly differentiated squamous cell carcinoma (SCC) and shown to activate extracellular matrix adhesion and inhibit keratinocyte differentiation in vitro. To study its contribution to tumor development, we overexpressed the mutant or wild-type (WT) human β1 subunit in the basal layer of mouse epidermis using the keratin 14 promoter. The transgenic integrins were expressed at the cell surface and were functional, with the T188Iβ1 subunit promoting cell spreading to a greater extent than WTβ1. Epidermal proliferation and differentiation were unaffected and no expansion of the stem cell compartment was detected. During chemical carcinogenesis, both transgenes increased papilloma formation, but only the T188Iβ1 transgene stimulated the conversion of papillomas to SCCs. Papillomas bearing the mutation showed increased Erk activity and reduced differentiation. SCCs expressing T188Iβ1 were less well-differentiated than those expressing WTβ1. These observations establish that the expression of a genetic variant in the I-like domain of β1 integrins does not affect normal epidermal homeostasis, but increases tumor susceptibility and influences tumor type. [Cancer Res 2009;69(4):1334–42]