We seek to understand molecular regulatory mechanisms controlling breast tissue development andtransformation. SWI/SNF chromatin remodeling enzymes control the accessibility of genomic chromatin andare vitally important in the initiation of multiple differentiation programmes through regulation of cell cycleprogresson and gene expression. These enzymes interact with tumor suppressors, and individual subunitsare tumor suppressors themselves. The Runx2 transcriptional regulator plays an essential role indsteogenesis and is expressed at greatly elevated levels in breast and other cancer cells. The oncogenicpotential of Runx family members is an emerging theme in the characterization of numerous tumor types.Our preliminary studies indicate that both SWI/SNF enzymes and the Runx2 factor can modulate geneexpression, nuclear and cellular morphology, and tissue development in breast cells. Since developmentand malignant transformation take place in a three dimensional context, we are utilizing model systems ofnormal and transformed breast cells that recapitulate the microenvironment of a tissue and that permit thedynamic and reciprocal crosstalk between the extracellular matrix and nuclear gene expression. The fidelityof these systems to in vivo breast biology is essential to our efforts to understand regulatory mechanismscontrolling normal and tumorigenic processes in breast cells.We will define the requirements for SWI/SNF chromatin remodeling enzymes (Aim 1) and Runx2 (Aim 2) innormal and transformed tissue formation using breast epithelial cells grown in a three dimensional,reconstituted basement membrane culture by exploring how these factors affect the interplay betweensignaling from the tissue microenvironment and nuclear gene expression. Additionally, we will address howthese factors cooperate (Aim 3) in highly transformed breast cell lines to promote metastatic phenotypes.LAY SUMMARY: The relationship between molecular factors controlling cell growth and development andthe three dimensional environment in which the cells of a tissue exist has only recently begun to beinvestigated. We seek to understand how molecular regulatory factors and the tissue microenvirnmentcontribute to normal breast development as well as to the development of breast cancer.
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