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 mediate adhesion to either components of the extracellular matrix or to other cells. The beta1 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 the contributions of altered integrin receptor expression to the invasive and metastatic phenotype have been the primary focus of our lab, as well as a number of other laboratories. The alpha2beta1 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 other investigators made the key observation that alpha2beta1 integrin expression is decreased in adenocarcinoma of the breast in a manner that correlates with the stage of differentiation. Studies of other adenocarcinomas have yielded similar results. When the alpha2beta1 integrin was reexpressed in a poorly differentiated mammary carcinoma that expressed no detectable alpha2 integrin subunit, a dramatic reversion of malignant phenotype to a differentiated epithelial phenotype was observed, indicating a critical role for alpha2beta1 expression in mammary gland differentiation. Other laboratories using monoclonal antibodies to competitively inhibit alpha2beta1 integrin adhesion or oncogenic transformation using c-erb2 have confirmed the important role of that alpha2beta1 integrin in mammary gland morphogenesis. Re-expression of the alpha2beta1 integrin also results in upregulation of both the alpha6 and beta4 integrin subunits. To determine the contribution of enhanced alpha6 and beta4 integrin expression to the abrogation of the malignant phenotype by alpha2beta1 integrin expression, we have now separately re-expressed the human alpha6 or beta4 integrin subunit in the breast cancer model.