SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium.
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.
Marlow
Rebecca
R
Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California 95064, USA.
Strickland
Phyllis
P
Lee
Ji Shin
JS
Wu
Xinyan
X
Pebenito
Milana
M
Binnewies
Mikhail
M
Le
Elizabeth K
EK
Moran
Angel
A
Macias
Hector
H
Cardiff
Robert D
RD
Sukumar
Saraswati
S
Hinck
Lindsay
L
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D042361:Mammary Glands, Human / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D054377:Chemokine CXCL12; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019718:Receptors, CXCR4; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C492289:SLIT1 protein, human; C498990:SLIT3 protein, human