Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice

Elena Iavnilovitch, Robert Cardiff, Bernd Groner, Itamar Barash

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)607-619
Number of pages13
JournalInternational Journal of Cancer
Volume112
Issue number4
DOIs
StatePublished - Nov 20 2004

Keywords

  • Cancer
  • Mammary gland
  • Oncogene
  • Stat5
  • Transgenic mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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