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The finding that special AT-rich sequence binding protein 1 (SATB1) orchestrates global gene expression could change the way we view breast cancer development says the team of researchers from the University of California in Berkeley, USA.
"Our findings suggest a new paradigm in tumor progression, in which SATB1 functions as a genome organizer during tumorigenesis to reprogram expression and promote metastasis," Terumi Kohwi-Shigematsu and colleagues comment in the journal Nature.
Until recently, it was widely believed that metastatic cells were rare and evolved during late stages of tumor progression through a series of genetic changes.
The current prevailing view, however, is that a small number of cells in some primary tumors are predisposed to form tumor metastasis early in development - a view supported by gene expression analysis, which has revealed metastatic gene signatures in early-stage tumors.
SATB1 is a nuclear protein known for its role in regulating chromatin architecture in developing T-cells and has emerged as a candidate marker in breast cancer.
The researchers began by studying the expression of SATB1 in metastatic and non-metastatic cell lines grown in vitro. They found that SATB1 protein and messenger RNA were only detected in the metastatic cell lines.
In addition, they found elevated SATB1 protein expression in 16 poorly differentiated infiltrating ductal tumor samples but minimal or no expression in 12 non-malignant breast tissue samples.
The researchers then looked at the expression of SATB1 in the archived tumor samples of 1318 women with breast cancer for whom there was full clinical follow-up data. Kaplan-Meier analysis revealed a significant correlation between higher SABT1 expression levels and shorter overall survival.
Next, the researchers performed gene microarray analysis comparing global gene changes in cells that differentially expressed SATB1.
They found that SATB1 appeared to reprogram the expression of around 1000 genes including many know to be involved in oncogenic pathways such as vascular endothelial growth factors, matrix metalloproteases, transforming growth factor-β1, and epidermal growth factors.
Finally, the researchers blocked SATB1 gene expression in highly invasive breast cancer cell using short hairpin antisense RNAs and found that their capacity for proliferation and migration was reduced 80-85%.
Kohwi-Shigematsu et al say that by altering the gene expression profile of breast cancer cells, SATB1 is able to induce an aggressive phenotype that promotes both tumor growth and metastasis.
However, the question remains how SABTB1 is able to elicit such a profound effect.
They speculate that the answer lies with SABTB1's chromatin remodeling function and its ability to tether hundreds of gene loci to its regulatory network and assemble transcription factors.
Nature 2008; 452: 187-195
http://www.nature.com/nature/journal/v452/n7184/abs/nature06781.html
© 2008 CMG
18 March 2008
Master regulator of breast cancer metastases identified
MedWire News: Scientists have found a novel protein that acts as a master regulator in breast cancer by controlling the expression of over 1000 genes and promoting tumor growth and metastases.The finding that special AT-rich sequence binding protein 1 (SATB1) orchestrates global gene expression could change the way we view breast cancer development says the team of researchers from the University of California in Berkeley, USA.
"Our findings suggest a new paradigm in tumor progression, in which SATB1 functions as a genome organizer during tumorigenesis to reprogram expression and promote metastasis," Terumi Kohwi-Shigematsu and colleagues comment in the journal Nature.
Until recently, it was widely believed that metastatic cells were rare and evolved during late stages of tumor progression through a series of genetic changes.
The current prevailing view, however, is that a small number of cells in some primary tumors are predisposed to form tumor metastasis early in development - a view supported by gene expression analysis, which has revealed metastatic gene signatures in early-stage tumors.
SATB1 is a nuclear protein known for its role in regulating chromatin architecture in developing T-cells and has emerged as a candidate marker in breast cancer.
The researchers began by studying the expression of SATB1 in metastatic and non-metastatic cell lines grown in vitro. They found that SATB1 protein and messenger RNA were only detected in the metastatic cell lines.
In addition, they found elevated SATB1 protein expression in 16 poorly differentiated infiltrating ductal tumor samples but minimal or no expression in 12 non-malignant breast tissue samples.
The researchers then looked at the expression of SATB1 in the archived tumor samples of 1318 women with breast cancer for whom there was full clinical follow-up data. Kaplan-Meier analysis revealed a significant correlation between higher SABT1 expression levels and shorter overall survival.
Next, the researchers performed gene microarray analysis comparing global gene changes in cells that differentially expressed SATB1.
They found that SATB1 appeared to reprogram the expression of around 1000 genes including many know to be involved in oncogenic pathways such as vascular endothelial growth factors, matrix metalloproteases, transforming growth factor-β1, and epidermal growth factors.
Finally, the researchers blocked SATB1 gene expression in highly invasive breast cancer cell using short hairpin antisense RNAs and found that their capacity for proliferation and migration was reduced 80-85%.
Kohwi-Shigematsu et al say that by altering the gene expression profile of breast cancer cells, SATB1 is able to induce an aggressive phenotype that promotes both tumor growth and metastasis.
However, the question remains how SABTB1 is able to elicit such a profound effect.
They speculate that the answer lies with SABTB1's chromatin remodeling function and its ability to tether hundreds of gene loci to its regulatory network and assemble transcription factors.
Nature 2008; 452: 187-195
http://www.nature.com/nature/journal/v452/n7184/abs/nature06781.html
© 2008 CMG
Page last updated 2008-03-18
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