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Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2

Nature Cell Biology volume 9, pages 470–478 (2007)Cite this article

An Addendum to this article was published on 01 May 2007

Abstract

Aberrant constitutive expression of c-Rel, p65 and p50 NF-κB subunits has been reported in over 90% of breast cancers1,2. Recently, we characterized a de novo RelB NF-κB subunit synthesis pathway, induced by the cytomegalovirus (CMV) IE1 protein, in which binding of p50–p65 NF-κB and c-Jun–Fra-2 AP-1 complexes to the RELB promoter work in synergy to potently activate transcription3. Although RelB complexes were observed in mouse mammary tumours induced by either ectopic c-Rel expression4 or carcinogen exposure5, little is known about RelB in human breast disease. Here, we demonstrate constitutive de novo RelB synthesis is selectively active in invasive oestrogen receptor alpha (ERα)-negative breast cancer cells. ERα signalling reduced levels of functional NF-κB and Fra-2 AP-1 and inhibited de novo RelB synthesis, leading to an inverse correlation between RELB and ERα gene expression in human breast cancer tissues and cell lines. Induction of Bcl-2 by RelB promoted the more invasive phenotype of ERα-negative cancer cells. Thus, inhibition of de novo RelB synthesis represents a new mechanism whereby ERα controls epithelial to mesenchymal transition (EMT).

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Figure 1: RelB levels are inversely correlated with ERα status in breast cancer cells.
Figure 2: c-Jun–Fra-2 AP-1 and p50–p65 NF-κB complexes synergistically induce RELB promoter activity in ERα-negative breast cancer cells.
Figure 3: ERα represses NF-κB and AP-1 activities and reduces RelB levels.
Figure 4: RelB expression promotes mesenchymal phenotype of breast cancer cells.
Figure 5: Bcl-2 mediates control of invasive properties of breast cancer cells.

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References

  1. Nakshatri, H., Bhat-Nakshatri, P., Martin, D. A., Goulet, R. J., Jr. & Sledge, G. W., Jr. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol. 17, 3629–3639 (1997).

    Article  CAS  Google Scholar 

  2. Sovak, M. A. et al. Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J Clin. Invest. 100, 2952–2960 (1997).

    Article  CAS  Google Scholar 

  3. Wang, X. & Sonenshein, G. E. Induction of the RelB NF-kappaB subunit by the cytomegalovirus IE1 protein is mediated via Jun kinase and c-Jun/Fra-2 AP-1 complexes. J. Virol. 79, 95–105 (2005).

    Article  CAS  Google Scholar 

  4. Romieu-Mourez, R. et al. Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors. Mol. Cell Biol. 23, 5738–5754 (2003).

    Article  CAS  Google Scholar 

  5. Demicco, E. G. et al. RelB/p52 NF-kappaB complexes rescue an early delay in mammary gland development in transgenic mice with targeted superrepressor IkappaB-alpha expression and promote carcinogenesis of the mammary gland. Mol. Cell Biol. 25, 10136–10147 (2005).

    Article  CAS  Google Scholar 

  6. van de Vijver, M. J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).

    Article  CAS  Google Scholar 

  7. Wang, Y. et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365, 671–679 (2005).

    Article  CAS  Google Scholar 

  8. Philips, A. et al. FRA-1 expression level modulates regulation of activator protein-1 activity by estradiol in breast cancer cells. Mol. Endocrinol. 12, 973–985 (1998).

    Article  CAS  Google Scholar 

  9. Romieu-Mourez, R. et al. Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer. Cancer Res. 61, 3810–3818 (2001).

    CAS  PubMed  Google Scholar 

  10. Hyder, S. M., Chiappetta, C., Murthy, L. & Stancel, G. M. Selective inhibition of estrogen-regulated gene expression in vivo by the pure antiestrogen ICI 182,780. Cancer Res. 57, 2547–2549 (1997).

    CAS  PubMed  Google Scholar 

  11. Oliveira, C. A. et al. The antiestrogen ICI 182,780 decreases the expression of estrogen receptor-alpha but has no effect on estrogen receptor-beta and androgen receptor in rat efferent ductules. Reprod. Biol. Endocrinol. 1, 75 (2003).

    Article  Google Scholar 

  12. Kalaitzidis, D. & Gilmore, T. D. Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol. Metab. 16, 46–52 (2005).

    Article  CAS  Google Scholar 

  13. Horwitz, K. B. Mechanisms of hormone resistance in breast cancer. Breast Cancer Res. Treat. 26, 119–130 (1993).

    Article  CAS  Google Scholar 

  14. Johnston, S. R. et al. Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer. Cancer Res. 55, 3331–3338 (1995).

    CAS  PubMed  Google Scholar 

  15. Rochefort, H. et al. Estrogen receptor mediated inhibition of cancer cell invasion and motility: an overview. J. Steroid Biochem. Mol. Biol. 65, 163–168 (1998).

    Article  CAS  Google Scholar 

  16. Catz, S. D. & Johnson, J. L. Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 20, 7342–7351 (2001).

    Article  CAS  Google Scholar 

  17. Xiang, H., Wang, J. & Boxer, L. M. Role of the cyclic AMP response element in the bcl-2 promoter in the regulation of endogenous Bcl-2 expression and apoptosis in murine B cells. Mol. Cell Biol. 26, 8599–8606 (2006).

    Article  CAS  Google Scholar 

  18. Mehlen, P. & Puisieux, A. Metastasis: a question of life or death. Nature Rev. Cancer 6, 449–458 (2006).

    Article  CAS  Google Scholar 

  19. Burkly, L. et al. Expression of relB is required for the development of thymic medulla and dendritic cells. Nature 373, 531–536 (1995).

    Article  CAS  Google Scholar 

  20. Stoffel, A., Chaurushiya, M., Singh, B. & Levine, A. J. Activation of NF-kappaB and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis. Proc. Natl Acad. Sci. USA 101, 9079–9084 (2004).

    Article  CAS  Google Scholar 

  21. Lessard, L., Begin, L. R., Gleave, M. E., Mes-Masson, A. M. & Saad, F. Nuclear localisation of nuclear factor-kappaB transcription factors in prostate cancer: an immunohistochemical study. Br. J. Cancer 93, 1019–1023 (2005).

    Article  CAS  Google Scholar 

  22. Josson, S. et al. RelB regulates manganese superoxide dismutase gene and resistance to ionizing radiation of prostate cancer cells. Oncogene 25, 1554–1559 (2006).

    Article  CAS  Google Scholar 

  23. Van Laere, S. J. et al. Nuclear factor-kappaB signature of inflammatory breast cancer by cDNA microarray validated by quantitative real-time reverse transcription-PCR, immunohistochemistry, and nuclear factor-kappaB DNA-binding. Clin. Cancer Res. 12, 3249–3256 (2006).

    Article  CAS  Google Scholar 

  24. Huber, M. A. et al. NF-kappaB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression. J. Clin. Invest. 114, 569–581 (2004).

    Article  CAS  Google Scholar 

  25. Shin, S. R., Sanchez-Velar, N., Sherr, D. H. & Sonenshein, G. E. 7,12-dimethylbenz(a)anthracene treatment of a c-rel mouse mammary tumor cell line induces epithelial to mesenchymal transition via activation of nuclear factor-kappaB. Cancer Res. 66, 2570–2575 (2006).

    Article  CAS  Google Scholar 

  26. Schmitt, C. A. et al. Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 1, 289–298 (2002).

    Article  CAS  Google Scholar 

  27. de Moissac, D., Mustapha, S., Greenberg, A. H. & Kirshenbaum, L. A. Bcl-2 activates the transcription factor NFkappaB through the degradation of the cytoplasmic inhibitor IkappaBalpha. J. Biol. Chem. 273, 23946–23951 (1998).

    Article  CAS  Google Scholar 

  28. Fujita, N. et al. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 113, 207–219 (2003).

    Article  CAS  Google Scholar 

  29. Guo, S. & Sonenshein, G. E. Forkhead box transcription factor FOXO3a regulates estrogen receptor alpha expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway. Mol. Cell Biol. 24, 8681–8690 (2004).

    Article  CAS  Google Scholar 

  30. Philips, A., Chalbos, D. & Rochefort, H. Estradiol increases and anti-estrogens antagonize the growth factor-induced activator protein-1 activity in MCF7 breast cancer cells without affecting c-fos and c-jun synthesis. J. Biol. Chem. 268, 14103–14108 (1993).

    CAS  PubMed  Google Scholar 

  31. Romieu-Mourez, R., Landesman-Bollag, E., Seldin, D. C. & Sonenshein, G. E. Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Res. 62, 6770–6778 (2002).

    CAS  PubMed  Google Scholar 

  32. Min, C. et al. The tumor suppressor activity of the lysyl oxidase pro-peptide reverses invasive phenotype of Her-2/neu driven breast cancer. Cancer Res. 67, 1105–1112 (2007).

    Article  CAS  Google Scholar 

  33. Schjerven, H., Tran, T. N., Brandtzaeg, P. & Johansen, F. E. De novo synthesized RelB mediates TNF-induced up-regulation of the human polymeric Ig receptor. J. Immunol. 173, 1849–57 (2004).

    Article  CAS  Google Scholar 

  34. Sentman, C. L., Shutter, J. R., Hockenbery, D., Kanagawa, O. & Korsmeyer, S. J. Bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67, 879–888 (1991).

    Article  CAS  Google Scholar 

  35. Freund, A. et al. Mechanisms underlying differential expression of interleukin-8 in breast cancer cells. Oncogene 23, 6105–6114 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank F.-E. Johansen, C. V. Paya, S. Korsmeyer and L. M. Boxer for cloned DNAs, T. Akagi for the inducible retroviral vector, and P. Leder for the NF639 cell line. These studies were supported by National Institute of Health (NIH) grants ES11624 and CA36355.

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Authors and Affiliations

  1. Department of Biochemistry, Boston University School of Medicine, Boston, 02118, MA, USA

    Xiaobo Wang, Karine Belguise, Kathrin H. Kirsch & Gail E. Sonenshein

  2. Department of Pathology and Laboratory Medicine and the Women's Health Interdisciplinary Research Center, Boston University School of Medicine, Boston, 02118, MA, USA

    Nora D. Mineva

  3. Inserm, U540, Montpellier, F-34090 and Univ. Montpellier I, Montpellier, F-34000, France

    Nathalie Kersual, Florence Galtier & Dany Chalbos

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Wang, X., Belguise, K., Kersual, N. et al. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol 9, 470–478 (2007). https://doi.org/10.1038/ncb1559

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