SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium

Cancer Res. 2008 Oct 1;68(19):7819-27. doi: 10.1158/0008-5472.CAN-08-1357.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, CXCR4
  • Receptors, Immunologic
  • SLIT1 protein, human
  • SLIT3 protein, human
  • roundabout protein
  • Slit homolog 2 protein