ALTERED INTEGRIN EXPRESSION AND THE MALIGNANT PHENOTYPE - THE CONTRIBUTION OF MULTIPLE INTEGRATED INTEGRIN RECEPTORS

The integrins are a family of cell surface adhesion receptors that med iate adhesion to either components of the extracellular matrix or to o ther cells. The beta(1) family of integrins represent the major class of cell substrate receptors with specificities primarily for collagens , laminins, and fibronectins. The role of the integrin family of cell surface adhesion receptors in normal mammary gland morphogenesis and t he contributions of altered integrin receptor expression to the invasi ve and metastatic phenotype have been the primary focus of our lab, as well as a number of other laboratories. The alpha(2)beta(1) integrin is expressed at high levels by normal differentiated epithelial cells including those of the normal breast. Using breast cancer as a model, we evaluated changes in integrin expression in malignancy. We and othe r investigators made the key observation that alpha(2)beta(1) integrin expression is decreased in adenocarcinoma of the breast in a manner t hat correlates with the stage of differentiation. Studies of other ade nocarcinomas have yielded similar results. When the alpha(2)beta(1) in tegrin was reexpressed in a poorly differentiated mammary carcinoma th at expressed no detectable alpha(2) integrin subunit, a dramatic rever sion of malignant phenotype to a differentiated epithelial phenotype w as observed, indicating a critical role for alpha(2)beta(1) expression in mammary gland differentiation. Other laboratories using monoclonal antibodies to competitively inhibit alpha(2)beta(1) integrin adhesion or oncogenic transformation using c-erb2 have confirmed the important role of that alpha(2)beta(1) integrin in mammary gland morphogenesis. Re-expression of the alpha(2)beta(1) integrin also results in upregul ation of both the alpha(6) and beta(4) integrin subunits. To determine the contribution of enhanced alpha(6) and beta(4) integrin expression to the abrogation of the malignant phenotype by alpha(2)beta(1) integ rin expression, we have now separately re-expressed the human alpha(6) or beta(4) integrin subunit in the breast cancer model.