The long-term objectives of these studies are to elucidate the mechanisms by which hormones regulate the normal development of the mammary gland and milk protein gene expression, and to determine how these regulatory mechanisms have deviated in breast cancer. This proposal addresses the question of why the same hormones, which promote growth and terminal differentiation during normal mammary gland development, result in aberrant growth in the majority of breast tumors. Specific emphasis has been placed upon studying the mechanisms by which the lactogenic hormones, prolactin and glucocorticoids, regulate the expression of milk protein genes. These studies have established that composite response elements containing multiple binding sites for several transcription factors, including CCAAT/enhancer binding protein (C/EBP) beta, nuclear factor (NF) I, signal transducers and activators of transcription (Stat)5, and the glucocorticoid receptor (GR) mediate the hormonal and developmental regulation of milk protein gene expression. Analysis of C/EBP beta knockout (KO) mice revealed alterations not only in functional differentiation, but also surprisingly in ductal morphogenesis and lobuloalveolar development. These studies led to the hypothesis that steroid hormone regulated mammary epithelial cell (MEC) proliferation occurs via paracrine/juxtacrine mechanisms mediated by local growth factors, and that a switch to an autocrine signaling mechanism is an early event in the progression to breast cancer. To test this hypothesis we propose to combine mouse genetics with the in situ analysis of signal transduction pathways. Transgenic, conditional KO and KO-transplant mouse models will be employed for these studies. The following specific aims are proposed: 1. To elucidate the mechanisms by which C/EBP beta regulates ductal morphogenesis and lobuloalveolar development. 2. To analyze steroid receptor distribution, cell proliferation and local growth factor expression in several KO mice known to affect lobuloalveolar development, including PrlR, Stat5 A & B and p27 KO mice. 3. To utilize a novel, ligand-independent, drug inducible fibroblast growth factor receptor transgenic mouse model to understand the role of local growth factors in cell proliferation and lobuloalveolar development. 4. To utilize novel transgenic and conditional mouse models to study the role of beta-catenin in mediating Wnt signaling during mammary gland development. 5. To understand the role of C/EBP beta, Stat5 and GR in hormonally regulated chromatin remodeling.
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