Mechanism of Abnormal Cell-Extracellular Matrix Interactions in Human Breast Cancer.

Abstract

Abstract : Message levels of premalignant (S2) and tumorigenic (T4-2) cells, two sublines of a human breast cancer series, were compared to identify molecules marking the final events in malignant transformation. A novel gene Az-i expressed at a >10-fold higher level in S2 than in T4-2 cells was isolated. While Az-i message was present in nonmalignant breast cell lines, primary luminal epithelial cells, and cells from reduction mammoplasty, it was drastically downregulated or absent in ten mammary carcinoma cell lines and four breast carcinomabiopsies. Ectopically-expressed Az- 1 in T4-2 cells reverted them to a normal-like phenotype in a three-dimensional basement membrane culture. interestingly, upregulation of Az-i message was also correlated with phenotypic normalization of breast tumor cells in a % 1 -integrin reversion system. Furthermore, Az-i stably- transfected T4-2 cells were 80% less invasive and clonogenic in matrigel invasion and colony-forming assays, respectively, than the vector transfectants. Second structure predictions indicated that C-terminus of Az-i is homologous to the rod domain of plakin family, the versatile organizers of cytoskeletal architecture. These data suggest that Az-i may participate in the cytoskeletal organization of breast epithelial cells and Az-i may provide a link to the understanding of the abnormal cell-cell and cell-extracellular matrix interactions in the breast tumor cells.