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A role for dystroglycan in epithelial polarization: loss of function in breast tumor cells
John Muschler1, Dinah Levy, Roseanne Boudreau
1Division of Life Sciences, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. Muschler@cooper.cpmc.org
Abstract:
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.
Insights
Loss of dystroglycan (DG) function in breast cancer cells impairs their response to the basement membrane, contributing to tumor growth. Restoring DG function reduces mammary tumor cell tumorigenicity.
Area of Science:
- Cell Biology
- Cancer Research
- Extracellular Matrix Biology
Background:
- Cell-basement membrane interactions regulate epithelial cell behavior.
- Altered basement membrane signaling is linked to carcinoma cell abnormalities.
- Dystroglycan (DG) is a key receptor mediating these interactions.
Purpose of the Study:
- Investigate the role of dystroglycan (DG) in mammary epithelial cell function.
- Determine the significance of DG functional loss in breast tumor cell lines.
- Assess the impact of DG restoration on mammary tumor cell behavior and tumorigenicity.
Main Methods:
- Analyzed DG expression (alpha-DG and beta-DG) in nonmalignant and malignant mammary epithelial cell lines.
- Correlated alpha-DG levels with cell polarization in response to basement membrane.
- Overexpressed DG cDNA in a breast carcinoma cell line (HMT-3522-T4-2) to restore DG function.
- Evaluated the effect of DG restoration on cell polarization, cytoskeletal organization, growth control, and tumorigenic potential in vivo.
Main Results:
- Nonmalignant mammary epithelial cells express functional DG.
- While DG is expressed in breast carcinoma cell lines (beta-DG positive), alpha-DG is functionally diminished in most.
- High alpha-DG levels correlate with cell polarization.
- DG restoration in HMT-3522-T4-2 cells normalized cytoskeletal changes, polarization, and growth restriction.
- Restored DG function significantly reduced the tumorigenic potential of these cells in nude mice.
Conclusions:
- Dystroglycan (DG) is a critical mediator of normal cell responses to the basement membrane.
- Functional loss of DG is a significant factor in breast carcinoma cells.
- Impaired DG function contributes to aberrant mammary tumor cell behavior and increased tumorigenicity.