Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DCC loss does not affect latency of p53-deficient mammary tumour development.
Figure 2: Microphotographs of primary mammary carcinosarcoma (left) and metastasis in the lung (right) in serial sections.
Figure 3: DCC controls apoptosis induction in p53-deficient tumour cells in vitro and survival in vivo.

Similar content being viewed by others

References

  1. Fearon, E. R. et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science 247, 49–56 (1990)

    Article  ADS  CAS  Google Scholar 

  2. Keino-Masu, K. et al. Deleted in colorectal cancer (DCC) encodes a netrin receptor. Cell 87, 175–185 (1996)

    Article  CAS  Google Scholar 

  3. Serafini, T. et al. Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system. Cell 87, 1001–1014 (1996)

    Article  CAS  Google Scholar 

  4. 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)

    Article  CAS  Google Scholar 

  5. Mehlen, P. et al. The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. Nature 395, 801–804 (1998)

    Article  ADS  CAS  Google Scholar 

  6. 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)

    Article  ADS  CAS  Google Scholar 

  7. 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)

    Article  CAS  Google Scholar 

  8. 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)

    Article  ADS  CAS  Google Scholar 

  9. Mazelin, L. et al. Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 431, 80–84 (2004)

    Article  ADS  CAS  Google Scholar 

  10. Mehlen, P. & Fearon, E. R. Role of the dependence receptor DCC in colorectal cancer pathogenesis. J. Clin. Oncol. 22, 3420–3428 (2004)

    Article  CAS  Google Scholar 

  11. Hibi, K. et al. Aberrant methylation of the UNC5C gene is frequently detected in advanced colorectal cancer. Anticancer Res. 29, 271–273 (2009)

    CAS  PubMed  Google Scholar 

  12. 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)

    Article  CAS  Google Scholar 

  13. 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)

    PubMed  Google Scholar 

  14. Cho, K. R. et al. The DCC gene: structural analysis and mutations in colorectal carcinomas. Genomics 19, 525–531 (1994)

    Article  CAS  Google Scholar 

  15. Fazeli, A. et al. Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. Nature 386, 796–804 (1997)

    Article  ADS  CAS  Google Scholar 

  16. Roush, W. Putative cancer gene shows up in development instead. Science 276, 534–535 (1997)

    Article  CAS  Google Scholar 

  17. 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)

    Article  CAS  Google Scholar 

  18. 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)

    Article  ADS  CAS  Google Scholar 

  19. Tanikawa, C., Matsuda, K., Fukuda, S., Nakamura, Y. & Arakawa, H. p53RDL1 regulates p53-dependent apoptosis. Nature Cell Biol. 5, 216–223 (2003)

    Article  CAS  Google Scholar 

  20. 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)

    Article  CAS  Google Scholar 

  21. 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)

    CAS  PubMed  Google Scholar 

  22. 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)

    Article  CAS  Google Scholar 

  23. 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)

    Article  CAS  Google Scholar 

  24. 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)

    Article  CAS  Google Scholar 

  25. Hamamoto, T. et al. Compound disruption of Smad2 accelerates malignant progression of intestinal tumors in Apc knockout mice. Cancer Res. 62, 5955–5961 (2002)

    CAS  PubMed  Google Scholar 

  26. Alberici, P. et al. Smad4 haploinsufficiency in mouse models for intestinal cancer. Oncogene 25, 1841–1851 (2006)

    Article  CAS  Google Scholar 

  27. Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996)

    Article  CAS  Google Scholar 

  28. 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)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

J.Y.S. carried out the histopathological analysis, N.P. was involved in animal experiments and J.Z. performed the confocal microscopy. J.J. and A.B. participated in discussions and interpretations of the experiments. P.K. was responsible for the design and execution of the experiments, and P.K. and A.B. wrote the paper.

Corresponding author

Correspondence to Anton Berns.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-6 with legends and Supplementary Table 1. (PDF 19859 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krimpenfort, P., Song, JY., 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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10790

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer