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

Abstract

The mammary gland undergoes extensive tissue remodeling and cell death at the end of lactation in a process known as involution. We present evidence that the prolactin-activated transcription factor signal transducer and activator 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 involution, the absence of Stat5a facilitated involution-associated changes in morphology of the gland and the extent and timing of programmed cell death. These Stat5a-dependent changes also affected epidermal growth factor receptor-initiated mammary gland tumorigenesis. Overexpression of the transforming growth factor alpha transgene in the mammary epithelium reproducibly generated mammary hyperplasia and tumors. In the presence of the activated epidermal growth factor receptor, deletion of Stat5a delayed initial hyperplasia and mammary tumor development by 6 weeks. These observations demonstrate that Stat5a is a survival factor, and its presence is required for the epithelium of the mammary gland to resist regression and involution-mediated apoptosis. We also suggest that Stat5a is one of the antecedent, locally acting molecules that initiate the process of epithelial regression and reorganization during involution.