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Pdcd4 repression of lysyl oxidase inhibits hypoxia-induced breast cancer cell invasion

Oncogene volume 29, pages 3921–3932 (2010)Cite this article

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Abstract

Metastasis to bone, liver and lungs is the primary cause of death in breast cancer patients. Our studies have revealed that the novel tumor suppressor Pdcd4 inhibits breast cancer cell migration and invasion in vitro. Loss of Pdcd4 in human nonmetastatic breast cancer cells increased the expression of lysyl oxidase (LOX) mRNA. LOX is a hypoxia-inducible amine oxidase, the activity of which enhances breast cancer cell invasion in vitro and in vivo. Specific inhibition of LOX activity by β-aminopropionitrile or small interfering RNA decreased the invasiveness of T47D and MCF7 breast cancer cells attenuated for Pdcd4 function. Most significantly, loss of Pdcd4 augments hypoxia induction of LOX as well. Conversely, overexpression of Pdcd4 significantly reversed the hypoxia induction of LOX expression in T47D cells attenuated for Pdcd4. However, Pdcd4 did not affect hypoxia-inducible factor-1 (HIF-1) protein expression or HIF-1-responsive element-luciferase activity in response to hypoxia, suggesting that Pdcd4 regulation of LOX occurs through an HIF-independent mechanism. Nevertheless, the loss of Pdcd4 early in cancer progression may have an important role in the increased sensitivity of cancer cells to hypoxia through increased LOX activity and concomitant enhanced invasiveness.

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Acknowledgements

We thank Drs Giovanni Melillo and Annamaria Rapisarda (Tumor Hypoxia Laboratory, NCI-Frederick) for helpful suggestions and for the use of reagents and hypoxia chambers. We also thank members of the Gene Regulation Section, Laboratory of Cancer Prevention, for helpful discussions. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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  1. Gene Regulation Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA

    A N Santhanam, A R Baker, G Hegamyer & N H Colburn

  2. Children's Memorial Research Center, Cancer Biology and Epigenomics Program, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine at Northwestern University, Chicago, IL, USA

    D A Kirschmann

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Correspondence to A N Santhanam.

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Santhanam, A., Baker, A., Hegamyer, G. et al. Pdcd4 repression of lysyl oxidase inhibits hypoxia-induced breast cancer cell invasion. Oncogene 29, 3921–3932 (2010). https://doi.org/10.1038/onc.2010.158

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