Since its discovery in the early 1990s the deleted in colorectal cancer (DCC) gene, located on chromosome 18q21, has been proposed as a tumour suppressor gene as its loss is implicated in the majority of advanced colorectal and many other cancers1. DCC belongs to the family of netrin 1 receptors, which function as dependence receptors as they control survival or apoptosis depending on ligand binding. However, the role of DCC as a tumour suppressor remains controversial because of the rarity of DCC-specific mutations and the presence of other tumour suppressor genes in the same chromosomal region. Here we show that in a mouse model of mammary carcinoma based on somatic inactivation of p53, additional loss of DCC promotes metastasis formation without affecting the primary tumour phenotype. Furthermore, we demonstrate that in cell cultures derived from p53-deficient mouse mammary tumours DCC expression controls netrin-1-dependent cell survival, providing a mechanistic basis for the enhanced metastatic capacity of tumour cells lacking DCC. Consistent with this idea, in vivo tumour-cell survival is enhanced by DCC loss. Together, our data support the function of DCC as a context-dependent tumour suppressor that limits survival of disseminated tumour cells.
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Fearon, E. R. et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247, 49–56 (1990)
Keino-Masu, K. et al. Deleted in colorectal cancer (DCC) encodes a netrin receptor. Cell 87, 175–185 (1996)
Serafini, T. et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996)
Hong, K. et al. A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion. Cell 97, 927–941 (1999)
Mehlen, P. et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804 (1998)
Thiebault, K. et al. The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment. Proc. Natl Acad. Sci. USA 100, 4173–4178 (2003)
Delloye-Bourgeois, C. et al. Interference with netrin-1 and tumor cell death in non-small cell lung cancer. J. Natl Cancer Inst. 101, 237–247 (2009)
Fitamant, J. et al. Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer. Proc. Natl Acad. Sci. USA 105, 4850–4855 (2008)
Mazelin, L. et al. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 431, 80–84 (2004)
Mehlen, P. & Fearon, E. R. Role of the dependence receptor DCC in colorectal cancer pathogenesis. J. Clin. Oncol. 22, 3420–3428 (2004)
Hibi, K. et al. Aberrant methylation of the UNC5C gene is frequently detected in advanced colorectal cancer. Anticancer Res. 29, 271–273 (2009)
Shin, S. K. et al. Epigenetic and genetic alterations in netrin-1 receptors UNC5C and DCC in human colon cancer. Gastroenterology 133, 1849–1857 (2007)
Peltomäki, P. et al. Evidence supporting exclusion of the DCC gene and a portion of chromosome 18q as the locus for susceptibility to hereditary nonpolyposis colorectal carcinoma in five kindreds. Cancer Res. 51, 4135–4140 (1991)
Cho, K. R. et al. The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics 19, 525–531 (1994)
Fazeli, A. et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386, 796–804 (1997)
Roush, W. Putative cancer gene shows up in development instead. Science 276, 534–535 (1997)
Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nature Genet. 29, 418–425 (2001)
Liu, X. et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc. Natl Acad. Sci. USA 104, 12111–12116 (2007)
Tanikawa, C., Matsuda, K., Fukuda, S., Nakamura, Y. & Arakawa, H. p53RDL1 regulates p53-dependent apoptosis. Nature Cell Biol. 5, 216–223 (2003)
Wang, H. et al. A newly identified dependence receptor UNC5H4 is induced during DNA damage-mediated apoptosis and transcriptional target of tumor suppressor p53. Biochem. Biophys. Res. Commun. 370, 594–598 (2008)
Miyamoto, Y. et al. Identification of UNC5A as a novel transcriptional target of tumor suppressor p53 and a regulator of apoptosis. Int. J. Oncol. 36, 1253–1260 (2010)
Derksen, P. W. et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10, 437–449 (2006)
Volenec, A., Bhogal, R. K., Moorman, J. M., Leslie, R. A. & Flanigan, T. P. Differential expression of DCC mRNA in adult rat forebrain. Neuroreport 8, 2913–2917 (1997)
Livesey, F. J. & Hunt, S. P. Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. Mol. Cell. Neurosci. 8, 417–429 (1997)
Hamamoto, T. et al. Compound disruption of Smad2 accelerates malignant progression of intestinal tumors in Apc knockout mice. Cancer Res. 62, 5955–5961 (2002)
Alberici, P. et al. Smad4 haploinsufficiency in mouse models for intestinal cancer. Oncogene 25, 1841–1851 (2006)
Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996)
Austrup, F. et al. Prognostic value of genomic alterations in minimal residual cancer cells purified from the blood of breast cancer patients. Br. J. Cancer 83, 1664–1673 (2000)
We thank R. B. Ali for assistance in generating the mice, J. Blitz and the staff of the NKI animal facility for providing animal care, the staff of the histology department for the processing of tissues, I. Huijbers and H. van Zeeburg for help with apoptosis and FACS analysis, A. Kraft, S. Klarenbeek, S. Rottenberg and G. Doumont for discussions, and T. Braumuller and A. Kersbergen for technical support. We also thank the laboratory of P. Mehlen for the gift of netrin 1.
The authors declare no competing financial interests.
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Krimpenfort, P., Song, J., Proost, N. et al. Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours. Nature 482, 538–541 (2012). https://doi.org/10.1038/nature10790
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