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Function of the Integrin 6ß1 in Metastatic Breast Carcinoma Cells Assessed by Expression of a Dominant-Negative Receptor¹

Deaconess Hospital and Harvard Medical School, Boston, Massachusetts 02115 [L. M. S., C. C., A. M. M.], and Laboratory of Molecular Pathology, University Institute of Pathological Anatomy, DK-2100 Copenhagen, Denmark [U. M. W.]

The involvement of the 6ß1 integrin, a laminin receptor, in breast carcinoma progression needs to be addressed rigorously. We report that a human breast carcinoma cell line, MDA-MB-435, known to be highly invasive and metastatic, expresses three potential integrin laminin receptors: 2ß1, 3ß1, and 6ß1, but uses only 6ß1 to mediate adhesion and migration on laminin matrices. To investigate the contribution of 6ß1 to the aggressive behavior of these cells, we developed a dominant-negative strategy for knocking out 6ß1 function that involved expression of a cytoplasmic domain deletion mutant of the ß4 integrin subunit by cDNA transfection. Stable transfectants of MDA-MB-435 cells that expressed this mutant ß4 subunit were inhibited dramatically in their ability to adhere and migrate on laminin matrices, and their capacity to invade Matrigel was reduced significantly. These findings support the hypothesis that 6ß1 is important for breast cancer progression. Moreover, this approach is a powerful method that should be useful in assessing the role of 6ß1 in other cells.

¹ This work was supported by NIH Grant AI39264 and a NATO Collaborative Research Grant. L. S. is the recipient of U.S. Army Breast Cancer Fellowship DAMD17-94-J-4335. A. Mercurio is the recipient of an American Cancer Society Faculty Research Award. U. Wewer is supported by grants from the Danish Cancer Society.

² To whom requests for reprints should be addressed, at Laboratory of Cancer Biology, Deaconess Hospital and Harvard Medical School, 50 Binney Street, Boston, MA 02115. Phone: (617) 732-9874; Fax: (617) 738-9188.

Received 11/22/95. Accepted 1/16/96.

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