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PMID:18829537

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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

Significance

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


See also

References

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