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SLITs Suppress Tumor Growth In vivo by Silencing Sdf1/Cxcr4 within Breast Epithelium

¹ Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California; ² University of California Davis Center of Comparative Medicine, Davis, California; and ³ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Lindsay Hinck, Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064. Phone: 831-459-5253; Fax: 831-459-3139; E-mail: hinck{at}biology.ucsc.edu.

Key Words: CXCR4 • Robo • Slit

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. [Cancer Res 2008;68(19):7819–27]