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

Authors
  • R, Marlow
  • P, Strickland
  • Juhee Lee
  • X, Wu
  • M, Pebenito
  • M, Binnewies
  • Ek, Le
  • A, Moran
  • H, Macias
  • Rd, Cardiff
  • S, Sukumar
  • Lindsay Hinck
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Volume
68
Issue
19
Pages
7819–7827
Identifiers
DOI: 10.1158/0008-5472.CAN-08-1357
Source
UCSC Cancer biomedical-ucsc
License
Unknown

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.

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