REGULATORY MECHANISMS CONTROLLING BREAST TISSUE DEVELOPMENT AND TRANSFORMATION

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We seek to understand molecular regulatory mechanisms controlling breast tissue development and transformation. SWI/SNF chromatin remodeling enzymes control the accessibility of genomic chromatin and are vitally important in the initiation of multiple differentiation programmes through regulation of cell cycle progresson and gene expression. These enzymes interact with tumor suppressors, and individual subunits are tumor suppressors themselves. The Runx2 transcriptional regulator plays an essential role in dsteogenesis and is expressed at greatly elevated levels in breast and other cancer cells. The oncogenic potential 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 gene expression, nuclear and cellular morphology, and tissue development in breast cells. Since development and malignant transformation take place in a three dimensional context, we are utilizing model systems of normal and transformed breast cells that recapitulate the microenvironment of a tissue and that permit the dynamic and reciprocal crosstalk between the extracellular matrix and nuclear gene expression. The fidelity of these systems to in vivo breast biology is essential to our efforts to understand regulatory mechanisms controlling normal and tumorigenic processes in breast cells. We will define the requirements for SWI/SNF chromatin remodeling enzymes (Aim 1) and Runx2 (Aim 2) in normal 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 between signaling from the tissue microenvironment and nuclear gene expression. Additionally, we will address how these 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 and the three dimensional environment in which the cells of a tissue exist has only recently begun to be investigated. We seek to understand how molecular regulatory factors and the tissue microenvirnment contribute to normal breast development as well as to the development of breast cancer.