TY - JOUR
T1 - SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium
AU - Marlow, Rebecca
AU - Strickland, Phyllis
AU - Ji, Shin Lee
AU - Wu, Xinyan
AU - PeBenito, Milana
AU - Binnewies, Mikhail
AU - Le, Elizabeth K.
AU - Moran, Angel
AU - Macias, Hector
AU - Cardiff, Robert
AU - Sukumar, Saraswati
AU - Hinck, Lindsay
PY - 2008/10/1
Y1 - 2008/10/1
N2 - 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.
AB - 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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U2 - 10.1158/0008-5472.CAN-08-1357
DO - 10.1158/0008-5472.CAN-08-1357
M3 - Article
C2 - 18829537
AN - SCOPUS:54249159249
VL - 68
SP - 7819
EP - 7827
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 19
ER -