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Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer

Abstract

Inflammatory breast cancer (IBC) is the most lethal form of primary breast cancer1. IBC lethality derives from generation of tumour emboli, which are non-adherent cell clusters that rapidly spread by a form of continuous invasion known as passive metastasis2,3,4,5. In most cancers, expression of E-cadherin, an epithelial marker, is indicative of low metastatic potential6,7. In IBC, E-cadherin is overexpressed8 and supports formation of tumour emboli by promoting tumour cell interactions rather than adherence to stroma2,3,9. E-cadherin, a surface component of adherens junctions, is anchored by interaction with p120 catenin (p120). We show that the unique pathogenic properties of IBC result in part from overexpression of the translation initiation factor eIF4GI in most IBCs. eIF4GI reprograms the protein synthetic machinery for increased translation of mRNAs with internal ribosome entry sites (IRESs) that promote IBC tumour cell survival and formation of tumour emboli. Overexpression of eIF4GI promotes formation of IBC tumour emboli by enhancing translation of IRES-containing p120 mRNAs. These findings provide a new understanding of translational control in the development of advanced breast cancer.

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Figure 1: eIF4GI overexpression in IBC drives tumour growth.
Figure 2: Silencing of eIF4GI in SUM149 cells is associated with internalization and destabilization of E-cadherin.
Figure 3: Internalization and destabilization of E-cadherin after eIF4GI silencing results from specific reduction in the translation of p120 mRNA.
Figure 4: Role of eIF4GI overexpression in tumour growth and tumour cell emboli formation.

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Acknowledgements

We thank I. Mohr and members of the Schneider lab for their comments on the manuscript. This study was supported by the US Department of Defence Breast Cancer Center of Excellence Research Program (W81XWH-06-1-0629), the Breast Cancer Research Foundation (15-C6000-33141; R.J.S. and S.C.F.), Shifrin and Myers, the NY State Breast Cancer Research Fund (D.S.) and the Breast Cancer Discovery Fund.

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D.S., S.C.F. and R.J.S designed and organized the experiments and wrote the manuscript. D.S. performed most of the studies; R.A. and F.D performed the immunohistochemistry studies; J.G. and T.H. performed the statistical analysis; P.L. and L.Z obtained, verified and prepared the tissue for analysis.

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Correspondence to Robert J. Schneider.

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The authors declare no competing financial interests.

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Silvera, D., Arju, R., Darvishian, F. et al. Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer. Nat Cell Biol 11, 903–908 (2009). https://doi.org/10.1038/ncb1900

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