Signal transducer and activator of transcription 5a influences mammary epithelial cell survival and tumorigenesis

The mammary gland undergoes extensive tissue remodeling and cell death at t he end of lactation in a process known as involution. We present evidence t hat the prolactin-activated transcription factor signal transducer and acti vator of transcription 5a (Stat5a) has a crucial role in the regulation of cell death during mammary gland involution. In a transforming growth factor -alpha transgenic mouse model that exhibited delayed mammary gland involuti on, the absence of Stat5a facilitated involution-associated changes in morp hology of the gland and the extent and timing of programmed cell death. The se Stat5a-dependent changes also affected epidermal growth factor receptor- initiated mammary gland tumorigenesis. Overexpression of the transforming g rowth factor alpha transgene in the mammary epithelium reproducibly generat ed mammary hyperplasia and tumors. In the presence of the activated epiderm al growth factor receptor, deletion of Stat5a delayed initial hyperplasia a nd mammary tumor development by 6 weeks. These observations demonstrate tha t Stat5a is a survival factor, and its presence is required for the epithel ium of the mammary gland to resist regression and involution-mediated apopt osis. We also suggest that Stat5a is one of the antecedent, locally acting molecules that initiate the process of epithelial regression and reorganiza tion during involution.