The role of the integrin family of heterodimeric transmembrane glycoproteins as the major mediators of adhesion between cells and the extracellular matrix is now well established. Our early studies established that the level of integrin expression is decreased in adeno- carcinoma of the breast in a manner that correlates with the histologic degree of differentiation. The most striking decreases were in the level of the alpha/2beta/1 integrin. Our recent experimental studies suggest that altered alpha/2beta/1 integrin receptor expression is an important determinant of the differentiated phenotype and that diminished alpha/2beta/1 expression contributes to the malignant behavior of breast cancer cells. In this proposal, we will examine two complementary models of altered alpha/2beta/1 integrin expression in breast cancer. In one model, de novo expression of the alpha/2beta/1 integrin by a poorly differentiated carcinoma of the breast that expresses no detectable alpha/2 mRNA or protein results in dramatic phenotypic alterations, confers the ability to form gland-like structures in three dimensional matrices, and diminishes the malignant potential in vivo. The complementary model utilizes the expression of anti-sense mRNA to diminish the alpha/2beta/1 integrin by a well-differentiated breast carcinoma cell, T47-D, that expresses high levels of the alpha/2beta/1 integrin and organizes into branching tubules in collagen matrices. Diminished expression of the alpha/2beta/1 integrin decreases adhesion to collagen and prevents glandular differentiation. Both gain and loss of function models indicate that the alpha/2beta/1 integrin is required for breast epithelial branching morphogenesis and that diminished alpha/2beta/1 integrin contributes to the invasive behavior of tumor cells in vitro. The experiments described in this proposal will directly establish the role of altered alpha/2beta/1 integrin in breast cancer in vivo and will begin to delineate the mechanisms by which alpha/2beta/1 integrin expression may alter epithelial differentiation and the expression of other genes. In vivo studies using the well-characterized models will be carried out in severe combined immunodeficiency mice. The role of the cytoplasmic tail of the alpha/2 integrin in signalling the observed phenotypic changes will be analyzed by the use of chimeric alpha/2 integrin cDNA constructs. The coordinate expression of other cell adhesion molecules associated with epithelial differentiation and whose expression is dependent upon alpha/2beta/1 integrin expression will be analyzed.
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