A role for dystroglycan in epithelial polarization: loss of function in breast tumor cells.
Receptors mediating cell-basement membrane interactions are potent regulators of epithelial architecture and function, and alterations in signals from the basement membrane are implicated in the aberrant behavior of carcinoma cells. In this study, we have investigated the role of the basement membrane receptor dystroglycan (DG) in mammary epithelial cell function, and the significance of loss of DG function in breast tumor cell lines. Nonmalignant mammary epithelial cells express a functional DG. Analysis of multiple breast carcinoma cell lines revealed that DG is expressed in all of the cell lines examined, as evidenced by beta-DG expression, but that alpha-DG is functionally diminished in the majority. High levels of alpha-DG correlated strongly with the ability of cells to polarize in the presence of the basement membrane. Overexpression of the DG cDNA in HMT-3522-T4-2 cells elevated alpha-DG levels and altered responsiveness to the basement membrane; DG overexpression restored the ability of the cells to undergo cytoskeletal changes, to polarize, and to restrict growth in response to basement membrane proteins. Moreover, restoration of DG function to these cells greatly reduced their tumorigenic potential in nude mice. These data point to DG as an important mediator of normal cell responses to the basement membrane, and as a significant variable in carcinoma cells, in which its frequent loss can contribute to aberrant cell behavior.
Muschler
John
J
Division of Life Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. Muschler@cooper.cpmc.org
Levy
Dinah
D
Boudreau
Roseanne
R
Henry
Michael
M
Campbell
Kevin
K
Bissell
Mina J
MJ
D001485:Basement Membrane / Q000378:metabolism / Q000502:physiology; D001940:Breast / Q000166:cytology / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism / Q000502:physiology; D049030:Dystroglycans; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D049030:Dystroglycans