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MYC suppresses cancer metastasis by direct transcriptional silencing of αv and β3 integrin subunits

Nature Cell Biology volume 14, pages 567–574 (2012)Cite this article

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Abstract

Overexpression of MYC transforms cells in culture, elicits malignant tumours in experimental animals and is found in many human tumours. We now report the paradoxical finding that this powerful oncogene can also act as a suppressor of cell motility, invasiveness and metastasis. Overexpression of MYC stimulated proliferation of breast cancer cells both in culture and in vivo as expected, but inhibited motility and invasiveness in culture, and lung and liver metastases in xenografted tumours. We show further that MYC represses transcription of both subunits of αvβ3 integrin, and that exogenous expression of β3 integrin in human breast cancer cells that do not express this integrin rescues invasiveness and migration when MYC is downregulated. These data uncover an unexpected function of MYC, provide an explanation for the hitherto puzzling literature on the relationship between MYC and metastasis, and reveal a variable that could influence the development of therapies that target MYC.

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Figure 1: Elevated MYC expression impedes the invasiveness of human breast cancer cells.
Figure 2: Elevated MYC expression inhibits metastasis of human breast cancer cells.
Figure 3: MYC modulates cell shape, actin cytoskeleton, focal adhesion formation, and adhesion to and migration towards ECM.
Figure 4: MYC downregulates the expression of αv and β3 integrin genes through binding to their proximal promoters.
Figure 5: MYC affects breast cancer cell invasiveness by suppressing integrin αv and β3subunits.
Figure 6: MYC and E-cadherin can prevent β3-integrin-induced invasion.

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Acknowledgements

We thank D. Cheresh, F. G. Giancotti, A. Goga and D. Sheppard for providing DNA constructs and cell lines. We are grateful to C-Y. Chen, L. Prentice and B. Edenfeld for help with histology and imaging. We thank D. Khauv for work with the ChIP assay, E. Miller for work with the orthotopic animal assay, M. Cichon for cloning constructs and M. Stallings-Mann for work with analysis of experiments. We also thank members of the Bishop, Bissell and Radisky laboratories for their constructive discussion and help. This work was financially supported initially by the George Williams Hooper Foundation (J.M.B.). The founder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Further support came from NIH (P50 CA091956) and the DoD (PC094054) (to E.S.R.); NCI CA122086, Susan B. Komen foundation grant FAS0703855 and the Mayo Clinic Breast Cancer SPORE grant CA116201 (to D.C.R.); the DoD (W81XWH0810736), NIH/NCI (R37CA064786, U01CA143233, U54CA143836 and U54CA126552) and the Department of Energy OBER Low Dose Radiation Program (contract no. DE-AC02-05CH1123) (to M.J.B.).

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Author notes

  1. Hong Liu

    Present address: Present address: Eureka Therapeutics Inc. 5858 Horton Street, Suite 362, Emeryville, California 94608, USA,

  2. Hong Liu and Derek C. Radisky: These authors contributed equally to this work

  3. Derek C. Radisky, Mina J. Bissell and J. Michael Bishop: Co-contributing laboratories

Authors and Affiliations

  1. G.W. Hooper Foundation, University of California at San Francisco, San Francisco, California 94143, USA

    Hong Liu, Dun Yang & J. Michael Bishop

  2. Mayo Clinic Cancer Center, Jacksonville, Florida 32224, USA

    Derek C. Radisky & Evette S. Radisky

  3. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA

    Ren Xu & Mina J. Bissell

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Contributions

H.L., D.C.R., D.Y., E.S.R., M.J.B. and J.M.B. designed the research; H.L., D.C.R., R.X., E.S.R. and D.Y. performed research; H.L., D.Y., D.C.R., E.S.R., M.J.B. and J.M.B. analysed data; H.L., D.C.R., M.J.B. and J.M.B. wrote the paper.

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Correspondence to Derek C. Radisky.

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Liu, H., Radisky, D., Yang, D. et al. MYC suppresses cancer metastasis by direct transcriptional silencing of αv and β3 integrin subunits. Nat Cell Biol 14, 567–574 (2012). https://doi.org/10.1038/ncb2491

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