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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Carcinoma / genetics
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Carcinoma / metabolism
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Carcinoma / pathology*
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Cell Proliferation
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Chemokine CXCL12 / genetics*
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Chemokine CXCL12 / metabolism
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Down-Regulation
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Gene Silencing / physiology*
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / physiology
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Mammary Glands, Human / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / physiology
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Mice
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Mice, Knockout
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Mice, Nude
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Receptors, CXCR4 / genetics*
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Receptors, CXCR4 / metabolism
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology
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Roundabout Proteins
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Transplantation, Heterologous
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Tumor Cells, Cultured
Substances
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CXCL12 protein, human
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CXCR4 protein, human
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Chemokine CXCL12
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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Receptors, CXCR4
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Receptors, Immunologic
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SLIT1 protein, human
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SLIT3 protein, human
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Slit homolog 2 protein