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SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium.
- Source :
-
Cancer research [Cancer Res] 2008 Oct 01; Vol. 68 (19), pp. 7819-27. - Publication Year :
- 2008
-
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.
- Subjects :
- Animals
Breast Neoplasms genetics
Breast Neoplasms metabolism
Carcinoma genetics
Carcinoma metabolism
Cell Proliferation
Chemokine CXCL12 metabolism
Down-Regulation
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
Receptors, CXCR4 metabolism
Receptors, Immunologic genetics
Receptors, Immunologic physiology
Transplantation, Heterologous
Tumor Cells, Cultured
Roundabout Proteins
Breast Neoplasms pathology
Carcinoma pathology
Chemokine CXCL12 genetics
Gene Silencing physiology
Nerve Tissue Proteins physiology
Receptors, CXCR4 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 68
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 18829537
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-08-1357