Restoration of positioning control following Disabled-2 expression in ovarian and breast tumor cells.
The physical interaction of epithelial cells with the basement membrane ensures correct positioning and acts as a survival factor for epithelial cells. Cells that detach from the basement membrane often undergo apoptosis; however, in carcinomas, this positional control is absent, permitting disorganized cell proliferation. In the majority of breast and ovarian carcinomas (85-90%), the expression of a candidate tumor suppressor, Disabled-2 (Dab2), is frequently lost. The Dab2-negative tumor cells are no longer in contact with an intact basement membrane, as indicated by the absence of collagen IV (in about 90% of cases). However, in the subset (10-15%) of ovarian tumors in which Dab2 expression is positive, the presence of a basement membrane-like structure around tumor cells was observed. Recombinant adenovirus-mediated expression of Dab2 was used in Dab2-negative ovarian and breast cancer cells, and re-expression of Dab2 was found to lead to cell death or growth arrest. Dab2 expression suppressed MAPK activation and c-fos expression. Plating the infected cells on a basement membrane matrigel rescued the cells from death and growth arrest. Thus, Dab2 exhibits a negative activity for cell growth and survival, which can be countered by attachment of the cells to basement membrane matrix. We conclude that Dab2 functions in cell positioning control and mediates the exigency for basement membrane attachment of epithelial cells. Loss of Dab2 may contribute to the basement membrane-independent, disorganized proliferation of tumor cells in ovarian and breast carcinomas.
Sheng
Z
Z
Department of Biochemistry and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Sun
W
W
Smith
E
E
Cohen
C
C
Sheng
Z
Z
Xu
X X
XX
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D001485:Basement Membrane; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D016764:Cell Polarity / Q000235:genetics*; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D003260:Contact Inhibition; D004338:Drug Combinations; D004847:Epithelial Cells / Q000166:cytology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D016762:Genes, fos; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology*; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011506:Proteins; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D004338:Drug Combinations; D007797:Laminin; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011506:Proteins; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C059485:matrigel; D003094:Collagen