REGULATORY MECHANISMS CONTROLLING BREAST TISSUE DEVELOPMENT AND TRANSFORMATION

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

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