PMID:18829537

Citation	Marlow, R, Strickland, P, Lee, JS, Wu, X, Pebenito, M, Binnewies, M, Le, EK, Moran, A, Macias, H, Cardiff, RD, Sukumar, S and Hinck, L (2008) SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium. Cancer Res. 68:7819-27
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.
Links	PubMed PMC3075571 Online version:10.1158/0008-5472.CAN-08-1357
Keywords	Animals; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Carcinoma/genetics; Carcinoma/metabolism; Carcinoma/pathology; Cell Proliferation; Chemokine CXCL12/genetics; Chemokine CXCL12/metabolism; Down-Regulation; Gene Silencing/physiology; Humans; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/physiology; Mammary Glands, Human/metabolism; Membrane Proteins/genetics; Membrane Proteins/physiology; Mice; Mice, Knockout; Mice, Nude; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/physiology; Receptors, CXCR4/genetics; Receptors, CXCR4/metabolism; Receptors, Immunologic/genetics; Receptors, Immunologic/physiology; Transplantation, Heterologous; Tumor Cells, Cultured
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:ROBO1	involved_in	GO:0008285: negative regulation of cell population proliferation	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:3043142	P		Seeded From UniProt	complete
MOUSE:SLIT2	involved_in	GO:0008285: negative regulation of cell population proliferation	ECO:0000316: genetic interaction evidence used in manual assertion	MGI:MGI:1315202	P		Seeded From UniProt	complete
MOUSE:SLIT2	involved_in	GO:0010629: negative regulation of gene expression	ECO:0000316: genetic interaction evidence used in manual assertion	MGI:MGI:1315202	P		Seeded From UniProt	complete
MOUSE:SLIT2	involved_in	GO:0001701: in utero embryonic development	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:2179460	P		Seeded From UniProt	complete
MOUSE:SLIT3	involved_in	GO:0008285: negative regulation of cell population proliferation	ECO:0000316: genetic interaction evidence used in manual assertion	MGI:MGI:1315205	P		Seeded From UniProt	complete
MOUSE:SLIT3	involved_in	GO:0010629: negative regulation of gene expression	ECO:0000316: genetic interaction evidence used in manual assertion	MGI:MGI:1315205	P		Seeded From UniProt	complete
HUMAN:ROBO1	involved_in	GO:0033600: negative regulation of mammary gland epithelial cell proliferation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ROBO1	involved_in	GO:0070100: negative regulation of chemokine-mediated signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ROBO1	involved_in	GO:0035385: Roundabout signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SLIT2	involved_in	GO:0070100: negative regulation of chemokine-mediated signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SLIT2	involved_in	GO:0035385: Roundabout signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SLIT2	involved_in	GO:0030308: negative regulation of cell growth	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SLIT3	involved_in	GO:0030308: negative regulation of cell growth	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SLIT3	involved_in	GO:0070100: negative regulation of chemokine-mediated signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:SLIT3	involved_in	GO:0035385: Roundabout signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:ROBO1	acts_upstream_of_or_within	GO:0008285: negative regulation of cell population proliferation	ECO:0000315: mutant phenotype evidence used in manual assertion	MGI:MGI:3043142	P		Seeded From UniProt	complete

References

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