Mechanisms of Abnormal Cell-Extracellular Matrix Interactions in Human Breast Cancer.
Annual rept. 1 Jul 94-30 Sep 95,
CALIFORNIA UNIV BERKELEY LAWRENCE BERKELEY LAB
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By a three-dimensional reconstituted basement membrane EHS matrix assay, we have previously shown that breast morphogenesis is regulated by cell-extracellular matrix ECM interactions and these contacts are impaired in malignancy. A series of studies were conducted to investigate the significance of cellECM interactions in tumorigenesis. ECM influences expression of lactoferrin, a differentiation marker, either by altering cell-cell interactions or by providing mechanochemical signals that regulate cell shape. Emphasis on the importance of intact beta-1-integrin signaling was indicated by function blocking studies. Phenotypically normal HMT-3522 cells failed to grow or differentiate and underwent apoptosis in the presence of beta-1 integrin blocking antibodies. In contrast a number of tumorigenic cell lines demonstrated refractoriness to these effects indicating they have circumvented this regulatory pathway. Finally the importance of cellECM interactions in the maintenance of the differentiated phenotype was underscored by examining the effects of overexpression of the putative tumor suppressor gene nm23-H1 in metastatic cell line MDA-MB- 435, where several aspects of normal breast morphogenesis was recapitulated. Further studies are presently underway to dissect other ECM components and their signaling pathways that are critical in breast cancer progression.
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