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WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells

Abstract

The WASF3 gene promotes invasion and metastasis in breast cancer cells, which have undergone epithelial-to-mesenchyme transition (EMT). Overexpression of WASF3 in cells that do not show EMT increases their invasion potential as a result of increased ZEB1/2 levels, which specifically suppress the anti-invasion chromosome 1 miR-200a/200b/429 cluster. ZEB1/2 upregulation by WASF3 results from downregulation of KISS1, leading to the release of inhibition of nuclear factor (NF)κB by IκBα. We further show that ZEB1 expression is regulated by the NFκB transcription factor. Knockdown of WASF3 in breast cancer cells leads to reduced ZEB1 levels and increased miR-200 and E-cadherin levels, resulting in loss of invasion potential. The central regulation of this interactive pathway by WASF3 accounts for the increased invasion associated with increased WASF3 expression seen in aggressive breast cancer cells. WASF3, therefore, is a potential target to suppress invasion and metastasis in breast cancer cells.

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Acknowledgements

We would like to thank Dr Leslie Ann Lesoon for the technical assistance and helpful comments during the writing of this manuscript. We also thank the staff of Cancer Center Shared Resources at GHSU for assistance during microarray data collection. Dr Cowell is supported by the Georgia Cancer Coalition as a distinguished cancer scholar and funded by the NIH. This study was supported, in part, by the National Institutes of Health Grant CA120510.

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Correspondence to Y Teng or J K Cowell.

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Teng, Y., Mei, Y., Hawthorn, L. et al. WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells. Oncogene 33, 203–211 (2014). https://doi.org/10.1038/onc.2012.565

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  • DOI: https://doi.org/10.1038/onc.2012.565

Keywords

  • breast cancer
  • metastasis
  • invasion
  • KISS1
  • WASF3
  • ZEB1

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