REVERSION OF THE MALIGNANT PHENOTYPE OF HUMAN BREAST CELLS IN 3-DIMENSIONAL CULTURE AND IN-VIVO BY INTEGRIN BLOCKING ANTIBODIES

In a recently developed human breast cancer model, treatment of tumor cells in a 3-dimensional culture with inhibitory beta 1-integrin antib ody or its Fab fragments led to a striking morphological and functiona l reversion to a normal phenotype. A stimulatory beta 1-integrin antib ody proved to be ineffective. The newly formed reverted acini re-assem bled a basement membrane and re-established E-cadherin-catenin complex es, and re-organized their cytoskeletons. At the same time they downre gulated cyclin D1, upregulated p21(cip,waf-1), and stopped growing. Tu mor cells treated with the same antibody and injected into nude mice h ad significantly reduced number and size of tumors in nude mice. The t issue 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, nonmalignan t cells when treated with either alpha 6 or beta 4 function altering a ntibodies continued to grow, and had disorganized colony morphologies resembling the untreated tumor colonies. This shows a significant role of the alpha 6/beta 4 heterodimer in directing polarity and tissue st ructure. The observed phenotypes were reversible when the cells were d isassociated and the antibodies removed, Our results illustrate that t he extracellular matrix and its receptors dictate the phenotype of mam mary epithelial cells, and thus in this model system the tissue phenot ype is dominant over the cellular genotype.