The a2b1 integrin serves as a collagen and/or laminin receptor on many cell types including the epithelial cells of the mammary gland. Our initial consideration of integrin expression in human solid tumors revealed that the a2b1 integrin was highly expressed on the epithelium of ducts and ductals of nonnal breast tissue, however. markedly reduced or undetectable levels of a2b1 integrin expression were seen in poorly-differentiated adenocarcinomas. Studies by a number of investigators confirmed our key observation that a2b1 integrin was decreased in adenocarcinoma of the breast as well as adenocarcinomas of the colon, prostate, lung, pancreas and skin. Loss of a2b1 integrin expression correlated directly with the loss of epithelial differentiation. The important role that a2b1 mtegrin plays in epithelial differentiation has been substantiated by a number of in vitro """"""""gain-of-function"""""""" and """"""""loss-of-function"""""""" models. These models support the essential role for a2b1 integrin expression in branching morphogenesis and in the organization of glandular structures. Based on the in vitro models, we hypothesize that the a2b1 integrin is uniquely responsible for controlling epithelial cell proliferation and differentiation by normal, i.e. non-transformed epithelial cells including those of the mammary gland. In addition, altered a2b1 integrin expression results in the loss of the differentiated epithelial phenotype and the acquisition of malignant behavior of breast cancer cells. This renewal proposal directly addresses these hypotheses in vivo by using genetically engineered mouse models.
The specific aims are (1) To determine in cz2-null mice the role of the a2b1 integrin during embryogenesis. (2) To determine in vivo the role of the a2b1 integrin in mammary gland development. (3) To determine in vivo the role of the a2b1 integrin in mammary gland tumorigenesis and breast cancer progression. This proposal directly addresses the Extraordinary Opportunities for Investment by the National Cancer Institute, including """"""""Defining the Signatures of Cancer Cells,"""""""" and """"""""Molecular Targets of Cancer.""""""""
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