Transcriptional regulation of apoptosis in mouse mammary gland

Postlactational regression of the mammary gland is characterized by extensive apoptosis of the epithelial compartment. Involution occurs in two phases: an early reversible phase and a later phase accompanied by breakdown of the extracellular matrix and remodeling of the gland. We have used both knockout mice and a cell-culture model to identify the transcription factors that regulate the early phase of involution. Conditional deletion of Stat3 results in diminished apoptosis and delayed involution, whereas, in contrast, loss of IRF-1, a downstream target of Stat1, accelerates the first phase of involution. We have begun to analyze in more detail the molecular events associated with the activation of these transcription factors. Downstream targets have not been identified, although IGFBP-5 may be an indirect target of both Stat3 and IRF-1. In the absence of Stat3, elevated levels of p21, p53 and Stat1 are observed. Using a mammary epithelial cell culture model, KIM-2, and inducible activation of Stat3 and Stat5, we have shown that dimerization of Stat3 alone is sufficient to induce apoptosis of KIM-2 cells. Furthermore, apoptosis can be significantly increased by blocking a survival pathway. In contrast, dimerization of Stat5 provides a differentiation signal and, subsequently, a survival signal for differentiated KIM-2 cells. Interplay between Stat3 and Stat5, identification of downstream targets, and crosstalk with other pathways is now being investigated.