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© The Rockefeller University Press, 0021-9525/1997//231 $5.00
The Journal of Cell Biology, Volume 137, Number 1, , 1997 231-245

Article

Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies



V.M. Weaver*, O.W. Petersen{ddagger}, F. Wang*, C.A. Larabell*, P. Briand§, C. Damsky||, and M.J. Bissell*

* Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, California 94720; {ddagger} Structural Cell Biology Unit, Institute of Medical Anatomy, The Panum Institute, DK-2200 Copenhagen N, Denmark; § Department of Tumor Endocrinology, Division of Cancer Biology, Danish Cancer Society, DK-2100, Copenhagen O, Denmark; and || Departments of Stomatology and Anatomy, University of California, San Francisco, California 94143

In a recently developed human breast cancer model, treatment of tumor cells in a 3-dimensional culture with inhibitory β1-integrin antibody or its Fab fragments led to a striking morphological and functional reversion to a normal phenotype. A stimulatory β1-integrin antibody proved to be ineffective. The newly formed reverted acini re-assembled a basement membrane and re-established E-cadherin–catenin complexes, and re-organized their cytoskeletons. At the same time they downregulated cyclin D1, upregulated p21cip,waf-1, and stopped growing. Tumor cells treated with the same antibody and injected into nude mice had significantly reduced number and size of tumors in nude mice. The tissue distribution of other integrins was also normalized, suggesting the existence of intimate interactions between the different integrin pathways as well as adherens junctions. On the other hand, nonmalignant cells when treated with either {alpha}6 or β4 function altering antibodies continued to grow, and had disorganized colony morphologies resembling the untreated tumor colonies. This shows a significant role of the {alpha}6/β4 heterodimer in directing polarity and tissue structure. The observed phenotypes were reversible when the cells were disassociated and the antibodies removed. Our results illustrate that the extracellular matrix and its receptors dictate the phenotype of mammary epithelial cells, and thus in this model system the tissue phenotype is dominant over the cellular genotype.

This work is based on ideas and research supported by the Office of Health and Environmental Research of the U.S. Department of Energy (currently under contract DE-AC03-SF00098, to M.J. Bissell). More recent efforts have been partially funded by a grant from the National Institutes of Health (CA-64786, to M.J. Bissell). V.M. Weaver was briefly supported by a grant from the U.S. Department of Defense (94MM4558) and subsequently by the Canadian Medical Research Council and is presently funded by the Breast Cancer Fund of the State of California (BCRP University of California-IFB-0400). O.W. Petersen is funded by the Danish Cancer Society (#95-100-44), the Thaysen Foundation, the Novo Foundation, and the Danish Medical Research Council (#9503681).

Please address all correspondence to Dr. Mina J. Bissell, Ernest Orlando Lawrence Berkeley National Laboratory, Mailstop 83-101, One Cyclotron Road, Berkeley, CA 94720. Tel.: (510) 486-4365. Fax: (510) 486-5586.

1. Abbreviations used in this paper: BM, basement membrane; MEC, mammary epithelial cell; 3-D, 3-dimensional.


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