Modulation of myoepithelial-associated alpha 6 beta 4 integrin in a breast cancer cell line alters invasive potential

In normal breast, cell-stromal contact is mediated by myoepithelial cells which strongly express mu 2 beta 1, alpha 3 beta 1, and alpha 6 beta 4 integrins, while epithelial cells exhibit alpha 2 beta 1 and alpha 3 beta 1 integrins at cell-cell borders, but do not express alpha 6 beta 4 integrin. Breast carcinomas consistently show down-regulation of all integrins. We have investigated the modulatory effect of stromal proteins, hormones, and transforming growth factor beta (TGF-beta) on integrin expression in breast cancer cell lines MCF-7, T47-D, and MDA-RIB 231 using indirect immunofluorescence and confocal laser scanning microscopy. MCF-7 and T47-D cells displayed low levels of both alpha 2 beta 1 and alpha 3 beta 1 integrins, and no alpha 6 beta 4 integrin, and this profile remained unchanged by modulatory agents. The MBA-MB 231 cells exhibited stronger staining for alpha 2 beta 1 and alpha 3 beta 1 integrins and focal staining for alpha 6 beta 4 integrin under control conditions, but markedly enhanced reactivity for the alpha 6 beta 4 complex in the presence of TGF-beta. This was associated with acquisition of a spread cellular morphology and localization of alpha 6 beta 4 at the cell periphery in a discrete punctate distribution. There was associated enhanced expression of epiligrin, the ligand for alpha 6 beta 4, with similar localization to the cell periphery. Cell invasion assays through a Matrigel barrier revealed significantly reduced invasive potential of TGF-beta-treated cells, an effect largely reversed following preincubation of the treated cells with anti-beta 4 integrin antibody. We conclude that alpha 6 beta 4 integrin can be up-regulated by TGF-beta and has an anti-invasive effect on MDA-MB 231 cells. In addition to alpha 6 beta 4, MBA-MB 231 cells exhibit other myoepithelial markers including cytokeratin 14, vimentin, and weak expression of CALLA. These findings support the concept of a subgroup of breast carcinomas displaying features of myoepithelial differentiation. (C) 1997 Academic Press.