Prevention of Breast Cancer by Targeting Myofibroblasts

University Of Alabama At Birmingham, Birmingham AL

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The structure and homeostasis of normal breast parenchyma is maintained by dynamic interactions between breast epithelial cells and their associated stroma. During breast carcinogenesis, these stromal-epithelial interactions are increasingly deregulated. Stromal fibroblasts in invasive breast carcinomas differ from fibroblasts associated with normal breast. These differences include the production of increased amounts of type-specific collagens, the over expression of various growth factors, proteases and protease inhibitors, and acquisition of the myofibroblast phenotype, characterized by alpha-smooth muscle actin (SMA) expression. At least a subset of these alterations in carcinoma associated fibroblasts (CAF), including the expression of SMA, is present in peri-ductal fibroblasts during breast carcinogenesis, prior to the development of invasive carcinoma. SMA functions to stop the migration of breast fibroblasts and contributes to the contraction of myofibroblasts. These activities involve alterations in adhesion molecules and cytoskeletal organization, which also affect expression of other molecules, such as extracellular matrix (ECM) proteins and proteases, by fibroblasts. In this proposal, we will test the hypotheses that 1) expression of SMA is responsible for much of the CAF phenotype and 2) SMA expression by CAF influences those fibroblast-epithelial cell interactions that regulate breast epithelial cell proliferation and invasion. RNA interference will be utilized to inhibit expression of SMA in CAF. SMA-inhibited and SMA-expressing CAF will be compared for 1) the expression of a variety of cell adhesion molecules, ECM proteins and ECM modulating proteases, as well as growth factors and cytokines and 2) the effect on growth and invasiveness of co-cultured breast epithelial cells. The goal of this proposal is to establish the potential of SMA as a key molecular target through which the fibroblast-epithelial cell interactions important in breast carcinogenesis can be modulated to prevent invasive breast carcinoma. [unreadable] [unreadable]