This laboratory investigates the genes and signaling pathways, which guide mammary development during puberty, pregnancy, lactation, involution and neoplasia. Both systemic endocrine hormones and local growth regulators control distinct phases of mammopoiesis. Gene deletion approaches were used to investigate the roles of prolactin (Prl), oxytocin (OT) and the transcription factor C/EBPbeta in the mammary gland. After binding to its receptor, Prl activates the Jak/Stat pathway and induces a developmental program. We have deleted the Stat5a gene from the mouse genome and demonstrated that Prl signaling through the Jak2/Stat5 pathway is essential for the proliferation and functional differentiation of lobulo-alveolar structures during pregnancy. Surprisingly, Stat5b, which is 96% conserved with Stat5a, is not required for mammary development and function. However, in the absence of Stat5a, extensive hormonal stimulation leads to the activation of Stat5b, which can partially compensate for the absence of Stat5a. Currently, the role of the Jak2/Stat5 pathway during mammary tumorigenesis is being investigated. Gene deletion studies also demonstrated that OT is not only required to facilitate milk ejection, but also for post-partum mammary development. In a quest to identify control genes, which function downstream and in response to systemic hormones, we analyzed mice from which the gene encoding the transcription factor C/EBPbeta has been deleted. In the absence of C/EBPbeta little mammary tissue develops during puberty and differentiation is blocked. C/EBPbeta appears to be a key control switch operating at early stages of mammary development. After weaning the secretory epithelium of the mammary gland is being remodeled and the epithelial cells are subject to programmed cell death. Bypassing such programmed cell death is considered a contributor to mammary tumorigenesis. We have identified members of the bcl-2 family, in particular bcl-x, as potential controls to initiate the remodeling process. Studying the role of bcl-x in mammary development through a gene deletion approach is not feasible since mice, which carry inactive bcl-x genes die during fetal development. To circumvent this stumbling block we established a Cre-loxP system, which allows us to delete genes specifically from mammary tissue. To this end we generated transgenic mice which carry the Cre recombinase gene under control of the promoter of the mammary-specific whey acidic protein gene. Experiments to specifically delete the bcl-x gene from mammary epithelial cells are in progress.
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