THE SUPRABASAL EXPRESSION OF ALPHA-6-BETA-4 INTEGRIN IS ASSOCIATED WITH A HIGH-RISK FOR MALIGNANT PROGRESSION IN MOUSE SKIN CARCINOGENESIS

Enhanced expression of the alpha6beta4 integrin complex has been linke d to malignant progression in mouse skin carcinogenesis. To determine if alpha6beta4 expression can predict risk for malignant conversion am ong populations of benign skin tumors, we analyzed the distribution of alpha6beta4 and other markers of progession in papillomas at high and low risk for malignant progression. After initiation with 7,12-dimeth ylbenz[a]anthracene, mice were promoted with 12-O-tetradecanoylphorbol -13-acetate to induce predominantly low risk tumors or promoted with m ezerein to produce predominantly high risk tumors. When tumors first a ppeared at 8 weeks after promotion, high risk papillomas demonstrated basal and suprabasal alpha6beta4 expression, loss of keratin 1, and ab errant expression of keratin 13. In these tumors alpha6beta4 expressio n coincided with an expansion of the proliferating compartment as indi cated by suprabasal bromodeoxyuridine labeling. In contrast, alpha6bet a4 immunostaining was confined to basal cells in low risk tumors, kera tin 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, alpha6beta4 suprabasal expression continued to distingu ish groups at higher risk for malignant conversion, but keratin 13 was expressed in all groups. At this time, high risk tumors displayed foc al expression of keratin 8 and gamma-glutamyltranspeptidase, markers a lso found in chemically induced carcinomas. Keratin 8 and gamma-glutam yltranspeptidase were expressed only in alpha6beta4 positive cells. Th ese results indicate that expression of alpha6beta4 integrin in suprab asal strata serves as an early predictive marker to identify benign sq uamous tumors at high risk for malignant progression.