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Cancer Res. 2008 Oct 1;68(19):7819-27. doi: 10.1158/0008-5472.CAN-08-1357.

SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium.

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  • 1Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California 95064, USA.

Erratum in

  • Cancer Res. 2010 May 1;70(9):3853.

Abstract

The genes encoding Slits and their Robo receptors are silenced in many types of cancer, including breast, suggesting a role for this signaling pathway in suppressing tumorigenesis. The molecular mechanism underlying these tumor-suppressive effects has not been delineated. Here, we show that loss of Slits, or their Robo1 receptor, in murine mammary gland or human breast carcinoma cells results in coordinate up-regulation of the Sdf1 and Cxcr4 signaling axis, specifically within mammary epithelium. This is accompanied by hyperplastic changes in cells and desmoplastic alterations in the surrounding stroma. A similar inverse correlation between Slit and Cxcr4 expression is identified in human breast tumor tissues. Furthermore, we show in a xenograft model that Slit overexpression down-regulates CXCR4 and dominantly suppresses tumor growth. These studies classify Slits as negative regulators of Sdf1 and Cxcr4 and identify a molecular signature in hyperplastic breast lesions that signifies inappropriate up-regulation of key prometastatic genes.

PMID:
18829537
[PubMed - indexed for MEDLINE]
PMCID:
PMC3075571
Free PMC Article
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