Stat transcription factors in mammary gland development and tumorigenesis

Two members of the Stat family of transcription factors play a vital role i n mouse mammary gland development. Stat5a was originally described as a reg ulator of milk protein gene expression and was subsequently shown to be ess ential for mammary development and lactogenesis. In contrast, Stat3 is an e ssential mediator of apoptosis and post-lactational regression. Other membe rs of the Stat family may have specific, but as yet undemonstrated, functio ns in mammary development. However, since Stat1 activity is regulated durin g mammary development in a pattern different from Stats 3 and 5, this facto r too may have a functional role. Although both Stat4 and Stat6 are express ed in mammary tissue, it seems unlikely that they will have a significant f unction as each of these Stats is activated in response to a limited number of cytokines. Given the essential regulatory roles of Stat signaling molec ules in mammary development, it was not surprising to discover that constit utively activated Stat factors are a feature of human breast cancers. Susta ined Stat activity has also been described in a variety of tumors including leukemias. The cause of this sustained activation is not clear but probabl y involves mutation of one of the many Stat regulatory proteins or dysregul ation of other signaling pathways which modulate Stat activity. It is now i mportant to understand the mechanism of constitutive Stat activity and to d evelop strategies which will abrogate aberrant Stat signaling in tumors in vivo.