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

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.

Vascular Robo4 restricts proangiogenic VEGF signaling in breast

“…3 A and B and Fig. S3 A-J) (27). There is growing evidence that SDF1 and VEGF collaborate to stimulate neoangiogenesis occurring in response to tumors, wounds, and chronic inflammatory disorders (28,30,31).…”

“…We performed immunohistochemical analysis on WT glands using anti-ROBO1 (27) and found it colocalized in a membrane-associated pattern with PECAM (Fig. 2B).…”

“…2B and Fig S2 C and D), raising the possibility that loss of Robo1 in the epithelium contributes to the observed increase in blood vessel density in the Robo1 −/− ;Robo4 −/− mice. Indeed, we previously showed that epithelial loss of Robo1 generates disorganized, hyperplastic tissue that is characterized by up-regulation of the chemokine CXCL12, also known as stromal derived factor-1 (SDF1) (27). SDF1 induces the expression of VEGF in breast cancer cell lines (28) and normal breast epithelium (Fig.…”

MicroRNA dysregulation in gastric cancer: a new player enters the game

“…Originally identified as a molecular mechanism of axon guidance, Slit/Robo1 signaling is now recognized to have a paradoxical role in carcinogenesis. Both oncogenic and tumor-suppressing functions of Slit/ Robo signaling have been reported (Wang et al, 2003;Schmid et al, 2007;Marlow et al, 2008;Stella et al, 2009;Yuasa-Kawada et al, 2009). In this respect, Tie et al (2010) reported that activation of Slit/Robo1 signaling induced by miR-218 downregulation triggers metastasis, whereas restoration of miR-218 expression inhibits invasion and metastasis of gastric cancer cells in vitro and in vivo.…”

Array-based profiling of the differential methylation status of CpG islands in hepatocellular carcinoma cell lines

“…Slit and Roundabout (Robo) were first identified as guidance molecules for neurons and leukocytes (28). More recently, their roles were expanded to include the mediation of angiogenesis, heart morphogenesis and tumor metastasis (29)(30)(31)(32). In vertebrates three Slit (Slit1, Slit2 and Slit3) and four Robo (Robo1, Robo2, Robo3/Rig-1 and Robo4/Magic Robo) genes have been identified (33).…”