Signal transducers and activators of transcription (Stats) are proteins that, as their name suggests, serve the dual function of signal transducers and activators of transcription in cells exposed to signaling polypeptides. This family now includes Stat1, Stat2, Stat3, Stat4, Stat5 (A and B) and Stat6. Over 30 different polypeptides have been identified as being able to activate the Stat family in various mammalian cells and the various Stats have now been implicated in a number of diseases. For example Stat3, Stat5, and Stat6 have been described as mediators of leptin which, as mentioned in a previous edition of TherapeuticAdvances contributes to conditions as diverse as obesity, cancer, osteoporosis and inflammation. Likewise, Stat5 has been identified as a key mediator of the response to T-cell activation with IL2. The range of immune cells and cytokines whose activity is modulated and/or mediated by Stat5 has since broadened considerably, linking Stat5 to various immulonological conditions. Stat5a was originally described as a regulator of milk protein gene expression and was subsequently shown to be essential for mammary development and lactogenesis. Given the essential regulatory roles of Stat signaling molecules in mammary development, and the role of Stat5a activation in mammary epithelial cell survival and differentiation, it was not surprising to discover that constitutively activated Stat factors are a feature of human breast cancers. Sustained Stat activity has also been described in a variety of tumors including leukemias. The cause of this sustained activation is not clear but probably involves mutation of one of the many Stat regulatory proteins or dysregulation of other signaling pathways which modulate Stat activity. Most recently, researchers at the Lombardi Cancer Center have reported the results of a genetic study of Stat5a involvement in mammary carcinogenesis. Similar to human breast cancers, a proportion of mammary adenocarcinomas in the WAP-TAg transgenic mouse model demonstrates constitutive Stat5a/b and Stat3 activation. Breeding WAP-TAg mice to mice carrying germ-line deletions of the Stat5a gene generated mice with reduced levels of Stat5a. Hemizygous loss of the Stat5a allele significantly reduced levels of Stat5a expression without altering mammary gland development or transgene expression levels. In comparison to mice carrying two wild-type Stat5a alleles, hemizygous loss of the Stat5a allele reduced the number of mice with palpable tumors and size of those tumors, and also delayed first tumor appearance and increased the apoptotic index in the adenocarcinomas. Neither cell proliferation nor differentiation in the cancers was altered. This body of evidence thus strongly suggests that decreasing Stat5 activation levels could be a therapeutic approach for reducing survival of breast cancer cells as well as the treatment of various immunological disorders.

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