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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References
Gong, Y. Pathologic aspects of inflammatory breast cancer: part 2. Biologic insights into its aggressive phenotype. Semin. Oncol. 35, 33–40 (2008).
Alpaugh, M. L., Tomlinson, J. S., Kasraeian, S. & Barsky, S. H. Cooperative role of E-cadherin and sialyl-Lewis X/A-deficient MUC1 in the passive dissemination of tumor emboli in inflammatory breast carcinoma. Oncogene 21, 3631–3643 (2002).
Colpaert, C. G. et al. Inflammatory breast cancer shows angiogenesis with high endothelial proliferation rate and strong E-cadherin expression. Br. J. Cancer 88, 718–725 (2003).
Liotta, L. A., Saidel, M. G. & Kleinerman, J. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res. 36, 889–894 (1976).
Moore, D. H., Rouse, M. B., Massenburg, G. S. & Zeman, E. M. Description of a spheroid model for the study of radiation and chemotherapy effects on hypoxic tumor cell populations. Gynecol. Oncol. 47, 44–47 (1992).
Parker, C. et al. E-cadherin as a prognostic indicator in primary breast cancer. Br. J. Cancer 85, 1958–1963 (2001).
Wheelock, M. J., Soler, A. P. & Knudsen, K. A. Cadherin junctions in mammary tumors. J. Mammary Gland Biol. Neoplasia 6, 275–285 (2001).
Kleer, C. G., van Golen, K. L., Braun, T. & Merajver, S. D. Persistent E-cadherin expression in inflammatory breast cancer. Mod. Pathol. 14, 458–464 (2001).
Tomlinson, J. S., Alpaugh, M. L. & Barsky, S. H. An intact overexpressed E-cadherin/α, β-catenin axis characterizes the lymphovascular emboli of inflammatory breast carcinoma. Cancer Res. 61, 5231–5241 (2001).
Schneider, R. J. & Sonenberg, N. Translational Control in Cancer Development and Progression in Translational Control in Biology and Medicine, (eds. Mathews, M. B., Sonenberg, N. & J. W. B. Hershey) 401–432 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2007).
Miyagi, Y. et al. Elevated levels of eukaryotic translation initiation factor eIF-4E, mRNA in a broad spectrum of transformed cell lines. Cancer Lett. 91, 247–252 (1995).
Rosenwald, I. B. et al. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 18, 2507–2517 (1999).
Rosenwald, I. B., Hutzler, M. J., Wang, S., Savas, L. & Fraire, A. E. Expression of eukaryotic translation initiation factors 4E and 2α is increased frequently in bronchioloalveolar but not in squamous cell carcinomas of the lung. Cancer 92, 2164–2171 (2001).
McClusky, D. R. et al. A prospective trial on initiation factor 4E (eIF4E) overexpression and cancer recurrence in node-positive breast cancer. Ann. Surg. 242, 584–590 (2005).
Gingras, A. C., Raught, B. & Sonenberg, N. mTOR signaling to translation. Curr. Top. Microbiol. Immunol. 279, 169–197 (2004).
Gingras, A. C., Raught, B. & Sonenberg, N. Regulation of translation initiation by FRAP/mTOR. Genes Dev. 15, 807–826 (2001).
Braunstein, S. et al. A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer. Mol. Cell 28, 501–512 (2007).
Ramírez-Valle, F. et al. eIF4GI links nutrient sensing to cell proliferation and inhibition of autophagy by selective mRNA translation. J. Cell Biol. 181, 293–307 (2008).
Portera, C. C. et al. Evaluation of E-cadherin expression and lymphatic involvement in inflammatory breast cancer. Breast Cancer Res. Treatment 100, S177 (2006).
Ignatoski, K. M., Lapointe, A. J., Radany, E. H. & Ethier, S. P. erbB-2 overexpression in human mammary epithelial cells confers growth factor independence. Endocrinology 140, 3615–3622 (1999).
Lerebours, F., Bieche, I. & Lidereau, R. Update on inflammatory breast cancer. Breast Cancer Res. 7, 52–58 (2005).
Bryant, D. M. & Stow, J. L. The ins and outs of E-cadherin trafficking. Trends Cell Biol. 14, 427–434 (2004).
Xiao, K., Oas, R. G., Chiasson, C. M. & Kowalczyk, A. P. Role of p120-catenin in cadherin trafficking. Biochim. Biophys. Acta 1773, 8–16 (2007).
Keirsebilck, A. et al. Molecular cloning of the human p120ctn catenin gene (CTNND1): expression of multiple alternatively spliced isoforms. Genomics 50, 129–146 (1998).
Lee, G. Y., Kenny, P. A., Lee, E. H. & Bissell, M. J. Three-dimensional culture models of normal and malignant breast epithelial cells. Nature Methods 4, 359–365 (2007).
Bauer, C. et al. Overexpression of the eukaryotic translation initiation factor 4G (eIF4G-1) in squamous cell lung carcinoma. Int. J. Cancer 98, 181–185 (2002).
Comtesse, N. et al. Frequent overexpression of the genes FXR1, CLAPM1 and EIF4G located on amplicon 3q26–27 in squamous cell carcinoma of the lung. Int. J. Cancer 120, 2538–2544 (2007).
van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. & Merajver, S. D. RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia 2, 418–425 (2000).
van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. W. & Merajver, S. D. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 60, 5832–5838 (2000).
van Golen, K. L. et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin. Cancer Res. 5, 2511–2519 (1999).
Cuesta, R., Laroia, G. & Schneider, R. J. Chaperone hsp27 inhibits translation during heat shock by binding eIF4G and facilitating dissociation of cap-initiation complexes. Genes Dev. 14, 1460–1470 (2000).
Brooks, P. C., Montgomery, A. M. & Cheresh, D. A. Use of the 10-day-old chick embryo model for studying angiogenesis. Methods Mol. Biol. 129, 257–269 (1999).
Stewart, S. A. et al. Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA 9, 493–501 (2003).
Xiao, K. et al. p120-Catenin regulates clathrin-dependent endocytosis of VE-cadherin. Mol. Biol. Cell. 16, 5141–5151 (2005).
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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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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DOI: https://doi.org/10.1038/ncb1900
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