posted on 2023-03-30, 18:22authored byRebecca Marlow, Phyllis Strickland, Ji Shin Lee, Xinyan Wu, Milana PeBenito, Mikhail Binnewies, Elizabeth K. Le, Angel Moran, Hector Macias, Robert D. Cardiff, Saraswati Sukumar, Lindsay Hinck
Supplementary Figure 4 from SLITs Suppress Tumor Growth In vivo by Silencing Sdf1/Cxcr4 within Breast Epithelium
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ARTICLE 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. [Cancer Res 2008;68(19):7819–27]