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Our previous studies demonstrated that reexpression of the alpha2beta1 integrin by a poorly differentiated breast carcinoma cell line, Mm5MT, resulted in dramatic reversion of a malignant phenotype to a differentiated epithelial phenotype. We hypothesized that reexpression of the alpha2beta1 integrin may regulate expression of other genes, the expression of which contributed to the dramatic phenotypic change. We now show that reexpression of the alpha2beta1 integrin results in up-regulation of both the alpha6 and beta4 integrin subunits but no change in the alpha1, alpha3, alpha5, or beta1 integrin subunits or E-cadherin. To further investigate the role of the alpha6 and beta4 integrin subunits in mediating the phenotypic changes elicited by reexpression of the alpha2beta1 integrin, the alpha6 or beta4 integrin subunit was expressed in our Mm5MT model. Expression of either subunit increased adhesion to laminin-1. Although adhesion to collagen was unaltered, contraction of three-dimensional collagen gels was reduced. Expression of either the alpha6 or beta4 integrin subunit also restored some aspects of a less malignant phenotype, including the acquisition of contact inhibition and diminution of anchorage-dependent and anchorage-independent growth rates. The alpha6 and beta4 transfectants formed three-dimensional organized structures when grown in gels of reconstituted basement membrane but did not form the highly branched, duct-like structures formed by the alpha2 transfectants. In contrast to the reduced invasiveness of the alpha2 transfectants, the alpha6 and beta4 transfectants retained an invasive phenotype. These results suggest that expression of the alpha6beta4 integrin contributes to some but not all of the phenotypic changes elicited by reexpression of the alpha2 integrin subunit and modulates the function of other integrins on these cells. Using our Mm5MT model, we are defining the cascade of integrin expression required for maintenance of the differentiated mammary epithelial cell phenotype.