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Downstream Events in Mammary Gland Morphogenesis Mediated by Reexpression of the ₂ß₁ Integrin: The Role of the ₆ and ß₄ Integrin Subunits¹

Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Our previous studies demonstrated that reexpression of the ₂ß₁ 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 ₂ß₁ integrin may regulate expression of other genes, the expression of which contributed to the dramatic phenotypic change. We now show that reexpression of the ₂ß₁ integrin results in up-regulation of both the ₆ and ß₄ integrin subunits but no change in the ₁, ₃, ₅, or ß₁ integrin subunits or E-cadherin. To further investigate the role of the ₆ and ß₄ integrin subunits in mediating the phenotypic changes elicited by reexpression of the ₂ß₁ integrin, the ₆ or ß₄ 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 ₆ or ß₄ 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 ₆ and ß₄ 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 ₂ transfectants. In contrast to the reduced invasiveness of the ₂ transfectants, the ₆ and ß₄ transfectants retained an invasive phenotype. These results suggest that expression of the ₆ß₄ integrin contributes to some but not all of the phenotypic changes elicited by reexpression of the ₂ 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.

¹ This work was supported by NIH Grant R01 CA70275.

² To whom requests for reprints should be addressed, at Department of Pathology, Washington University School of Medicine, 660 South Euclid, Box 8118, St. Louis, MO 63110. Phone: (314) 362-0108; Fax: (314) 747-2040.

Received 9/29/97. Accepted 3/18/98.

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