Unknown,Transcriptomics,Genomics,Proteomics

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SWI/SNF Chromatin-Remodeling Factor Smarcd3/Baf60c Controls Epithelial-Mesenchymal Transition by Inducing Wnt5a Signaling

ABSTRACT: We previously identified a gene signature predicted to regulate the epithelial-mesenchymal transition (EMT) in both epithelial tissue stem cells and breast cancer cells. A phenotypic RNA interference (RNAi) screen identified the genes within this 140-gene signature that promoted the conversion of mesenchymal epithelial cell adhesion molecule-negative (EpCAM-) breast cancer cells to an epithelial EpCAM+/high phenotype. The screen identified 10 of the 140 genes whose individual knockdown was sufficient to promote EpCAM and E-cadherin expression. Among these 10 genes, RNAi silencing of the SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c in EpCAM- breast cancer cells gave the most robust transition from the mesenchymal to epithelial phenotype. Conversely, expression of Smarcd3/Baf60c in immortalized human mammary epithelial cells induced an EMT. The mesenchymal-like phenotype promoted by Smarcd3/Baf60c expression resulted in gene expression changes in human mammary epithelial cells similar to that of claudin-low triple-negative breast cancer cells. These mammary epithelial cells expressing Smarcd3/Baf60c had upregulated Wnt5a expression. Inhibition of Wnt5a by either RNAi knockdown or blocking antibody reversed Smarcd3/Baf60c-induced EMT. Thus, Smarcd3/Baf60c epigenetically regulates EMT by activating WNT signaling pathways. sampleXreference

ORGANISM(S): Homo sapiens

SUBMITTER: Charles Perou

PROVIDER: E-GEOD-40145 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c controls epithelial-mesenchymal transition by inducing Wnt5a signaling.

Jordan Nicole Vincent NV Prat Aleix A Abell Amy N AN Zawistowski Jon S JS Sciaky Noah N Karginova Olga A OA Zhou Bingying B Golitz Brian T BT Perou Charles M CM Johnson Gary L GL

Molecular and cellular biology 20130528 15

We previously identified a gene signature predicted to regulate the epithelial-mesenchymal transition (EMT) in both epithelial tissue stem cells and breast cancer cells. A phenotypic RNA interference (RNAi) screen identified the genes within this 140-gene signature that promoted the conversion of mesenchymal epithelial cell adhesion molecule-negative (EpCAM-) breast cancer cells to an epithelial EpCAM+/high phenotype. The screen identified 10 of the 140 genes whose individual knockdown was suffi ...[more]

PMID: 23716599

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Project description:Introduction: Over the past several years, we have been interested in understanding the mechanisms by which hormone-dependent (HD) mammary carcinomas grow in the absence of the stimulatory hormone. We have hypothesized that the stromal compartment plays a pivotal role in the acquisition of the hormone-independent (HI) phenotype by providing stimulatory factors that replace the proliferative effects of the hormone. Methods: We used DNA microarrays to compare the gene expression profiles of tumors from the MPA mouse breast cancer model, one hormone-dependent (C4-HD) and one hormone-independent (C4-HI), using whole tumor samples or laser-captured purified stromal and epithelial cells obtained from the same tumors. The expression of selected genes was validated by immunohistochemistry and immunofluorescence assays. Results: We identified 413 genes that were expressed in tumor stroma but not in epithelial cells. Eighty-five percent of these genes were upregulated, whereas the remaining 15% were downregulated in C4-HI tumors relative to their expression in the C4-HD tumor stroma. Several matrix metallopeptidases, including Mmp13, Mmp3, Mmp10 and Mmp9, were overexpressed in the C4-HI tumor microenvironment. On the other hand, 1100 genes were specifically expressed in the tumor parenchyma. Among them, the 29% were upregulated, whereas the remaining 71% were downregulated, in C4-HI relative to C4-HD tumor epithelium. Steap, Pdgfc, Runx2, Cxcl9 and Sdf2 were among the genes with high expression in the C4-HI tumor parenchyma. Interestingly, we found that Fgf2 was one of the few genes upregulated by MPA in C4-HD tumors, confirming its pivotal role in regulating tumor growth in this model. Conclusions: We demonstrate a gene expression profile that distinguishes epithelial from stromal cells in mammary tumors with different hormone dependence. Our results support the hypothesis that the tumor-associated stroma may contribute to hormone-independent tumor growth. The fact that Fgf2 was one of these few stimulatory genes is worth investigating. reference X sample

Dataset Information

SWI/SNF Chromatin-Remodeling Factor Smarcd3/Baf60c Controls Epithelial-Mesenchymal Transition by Inducing Wnt5a Signaling

Publications

SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c controls epithelial-mesenchymal transition by inducing Wnt5a signaling.

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