The suprabasal expression of alpha 6 beta 4 integrin is associated with a high risk for malignant progression in...

Enhanced expression of the alpha 6 beta 4 integrin complex has been linked to malignant progression in mouse skin carcinogenesis. To determine if alpha 6 beta 4 expression can predict risk for malignant conversion among populations of benign skin tumors, we analyzed the distribution of alpha 6 beta 4 and other markers of progression in papillomas at high and low risk for malignant progression. After initiation with 7,12-dimethylbenz[a]anthracene, mice were promoted with 12-O-tetradecanoylphorbol-13-acetate to induce predominantly low risk tumors or promoted with mezerein to produce predominantly high risk tumors. When tumors first appeared at 8 weeks after promotion, high risk papillomas demonstrated basal and suprabasal alpha 6 beta 4 expression, loss of keratin 1, and aberrant expression of keratin 13. In these tumors alpha 6 beta 4 expression coincided with an expansion of the proliferating compartment as indicated by suprabasal bromodeoxyuridine labeling. In contrast, alpha 6 beta 4 immunostaining was confined to basal cells in low risk tumors, keratin 1 was abundant, and keratin 13 was absent in the majority of this group, while proliferating cells were largely in the basal compartment. By 33 weeks, alpha 6 beta 4 suprabasal expression continued to distinguish groups at higher risk for malignant conversion, but keratin 13 was expressed in all groups. At this time, high risk tumors displayed focal expression of keratin 8 and gamma-glutamyltranspeptidase, markers also found in chemically induced carcinomas. Keratin 8 and gamma-glutamyltranspeptidase were expressed only in alpha 6 beta 4 positive cells. These results indicate that expression of alpha 6 beta 4 integrin in suprabasal strata serves as an early predictive marker to identify benign squamous tumors at high risk for malignant progression.