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Oncogenes

Suppressive organization

Nature Reviews Cancer volume 7, page 731 (2007)Cite this article

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The human mammary epithelial cell line MCF-10A forms three-dimensional growth arrested acinus-like structures when cultured in the extracellular matrix extract Matrigel. Using MCF-10A cells expressing an activatable MYC construct (MYC-ERtm), the authors showed that chronic activation of MYC-ERtm, beginning a day after the cells are seeded in Matrigel, leads to increased proliferation and the formation of structures that are 1.4 times larger than normal. However, after about 15 days in culture the structures did not grow further, despite continued expression of MYC, and this was probably owing to increased apoptosis.

What happens if the acinar structures are allowed to form before MYC is activated? After 20 days in Matrigel culture (when the acini were growth arrested), activation of MYC-ERtm had no effect on the morphology, size or proliferation of the acini. Moreover, when the authors grew MYC-ERtm-expressing MCF-10A cells in collagen I cultures to form cysts without polarity or organization, they found that the activation of MYC-ERtm promoted proliferation in these unorganized structures, indicating that intact epithelial architecture is required to block MYC-induced proliferation. Short hairpin RNA (shRNA) that silenced the tumour suppressor LKB1 (a member of the Par family of cell polarity proteins) caused the formation of MCF-10A cell structures in Matrigel that were unorganized but still retained some aspects of polarity and still underwent growth arrest after 20 days. When MYC-ERtm was activated in these unorganized LKB1-deficient growth-arrested structures, the authors found that MYC was now able to induce proliferation.

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References

ORIGINAL RESEARCH PAPER

  1. Partanen, J. I., Nieminen, A. I., Makela, T. P. & Klefstrom, J. Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc. Natl Acad. Sci. USA 31 August 2007 (doi: 10.1073/pnas.0704,677,104)

FURTHER READING

  1. Debnath, J. & Brugge, J. S. Modelling glandular epithelial cancers in three-dimensional cultures. Nature Rev. Cancer 5, 675–688 (2005)

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Authors
  1. Sarah Seton-Rogers
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Seton-Rogers, S. Suppressive organization. Nat Rev Cancer 7, 731 (2007). https://doi.org/10.1038/nrc2238

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  • DOI: https://doi.org/10.1038/nrc2238

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