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Published on: January 3, 2013
SWI/SNF chromatin remodeling enzyme ATPases promote cell proliferation in normal mammary epithelial cells
Nathalie Cohet1, Kathleen M Stewart, Rajini Mudhasani
1Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Abstract:
The ATPase subunits of the SWI/SNF chromatin remodeling enzymes, Brahma (BRM) and Brahma-related gene 1 (BRG1), can induce cell cycle arrest in BRM and BRG1 deficient tumor cell lines, and mice heterozygous for Brg1 are pre-disposed to breast tumors, implicating loss of BRG1 as a mechanism for unregulated cell proliferation. To test the hypothesis that loss of BRG1 can contribute to breast cancer, we utilized RNA interference to reduce the amounts of BRM or BRG1 protein in the nonmalignant mammary epithelial cell line, MCF-10A. When grown in reconstituted basement membrane (rBM), these cells develop into acini that resemble the lobes of normal breast tissue. Contrary to expectations, knockdown of either BRM or BRG1 resulted in an inhibition of cell proliferation in monolayer cultures. This inhibition was strikingly enhanced in three-dimensional rBM culture, although some BRM-depleted cells were later able to resume proliferation. Cells did not arrest in any specific stage of the cell cycle; instead, the cell cycle length increased by approximately 50%. Thus, SWI/SNF ATPases promote cell cycle progression in nonmalignant mammary epithelial cells.
Insights
The SWI/SNF chromatin remodeling enzymes, Brahma (BRM) and Brahma-related gene 1 (BRG1), normally promote cell cycle progression. Loss of these ATPases inhibits proliferation in nonmalignant mammary cells, contrary to expectations for cancer development.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- SWI/SNF chromatin remodeling enzymes, including Brahma (BRM) and Brahma-related gene 1 (BRG1), are crucial for gene regulation.
- Loss of BRG1 is implicated in breast tumor predisposition and uncontrolled cell proliferation.
Purpose of the Study:
- To investigate the role of BRM and BRG1 in breast cancer development.
- To test the hypothesis that loss of BRG1 contributes to breast cancer by affecting cell proliferation.
Main Methods:
- Utilized RNA interference (RNAi) to deplete BRM or BRG1 protein levels in MCF-10A nonmalignant mammary epithelial cells.
- Cultured cells in monolayer and three-dimensional reconstituted basement membrane (rBM) to mimic normal breast tissue structures.
Main Results:
- Knockdown of BRM or BRG1 inhibited cell proliferation in monolayer cultures.
- This proliferation inhibition was significantly enhanced in 3D rBM cultures.
- Cells did not exhibit specific cell cycle arrest but showed a ~50% increase in cell cycle length.
Conclusions:
- Contrary to the hypothesis, SWI/SNF ATPases (BRM and BRG1) promote cell cycle progression in nonmalignant mammary epithelial cells.
- Loss of BRM or BRG1 function leads to cell proliferation defects, not uncontrolled growth, in this context.
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