Iavnilovitch, E., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet-Dagan, Israel
Cardiff, R.D., Center of Comparative Medicine, University of California at Davis, Davis, CA, United States
Groner, B., Georg Speyer Haus, Institute for Biomedical Research, Frankfurt am Main, Germany
Barash, I., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet-Dagan, Israel, Institute of Animal Science, ARO, Volcani Center, P.O. Box 6, Bet-Dagan 50250, Israel

Members of the signal transducers and activators of transcription (Stat) family regulate essential cellular growth and survival functions in normal cells and have also been implicated in tumorigenesis. We have studied the potential role of Stat5 in mammary tumorigenesis by targeting Stat5 variants to the mammary gland of transgenic mice using regulatory sequences of the β-lactoglobulin gene. Mammary-directed expression of the wild-type Stat5, constitutively activated Stat5 and carboxyl-terminally truncated dominant negative Stat5 forms resulted in mammary tumors with incidence rates of up to 22% and latency periods of 8-12 months. Undifferentiated carcinomas most frequently occurred in mice expressing the carboxyl-terminally truncated Stat5. The more differentiated papillary and micropapillary adenocarcinomas were primarily found in mice overexpressing the native and constitutively active transgenes. Higher levels of translation initiation factor 4E (elF4E) and cyclin DI expression but lower levels of activated Stat5 were found in tumors of mice expressing the constitutively active Stat5 when compared to mice expressing the wild-type or truncated forms. A higher expression of the estrogen receptor (ERα) was observed in carcinomas compared to other phenotypes. The ability of both forms of Stat5, the transactivating form and the dominant negative form, to participate in oncogenesis indicates that there is more than one mechanism by which Stat5 contributes to this process. The transactivation function of Stat5 is involved in the determination of tumors with a more differentiated phenotype. © 2004 Wiley-Liss, Inc.