The tumour suppressor C/EBPθ inhibits FBXW7 expression and promotes mammary tumour metastasis

Kuppusamy Balamurugan, Ju-Ming Wang, Hsin Hwa Tsai, Shikha Sharan, Miriam Anver, Robert Leighty, Esta Sterneck

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Inflammation and hypoxia are known to promote the metastatic progression of tumours. The CCAAT/enhancer-binding protein-θ (C/EBPθ, CEBPD) is an inflammatory response gene and candidate tumour suppressor, but its physiological role in tumourigenesis in vivo is unknown. Here, we demonstrate a tumour suppressor function of C/EBPθ using transgenic mice overexpressing the Neu/Her2/ERBB2 proto-oncogene in the mammary gland. Unexpectedly, this study also revealed that C/EBPθ is necessary for efficient tumour metastasis. We show that C/EBPθ is induced by hypoxia in tumours in vivo and in breast tumour cells in vitro, and that C/EBPθ-deficient cells exhibit reduced glycolytic metabolism and cell viability under hypoxia. C/EBPθ supports CXCR4 expression. On the other hand, C/EBPθ directly inhibits expression of the tumour suppressor F-box and WD repeat-domain containing 7 gene (FBXW7, FBW7, AGO, Cdc4), encoding an F-box protein that promotes degradation of the mammalian target of rapamycin (mTOR). Consequently, C/EBPθ enhances mTOR/AKT/S6K1 signalling and augments translation and activity of hypoxia-inducible factor-1α (HIF-1α), which is necessary for hypoxia adaptation. This work provides new insight into the mechanisms by which metastasis-promoting signals are induced specifically under hypoxia.

Original languageEnglish
Pages (from-to)4106-4117
Number of pages12
JournalEMBO Journal
Volume29
Issue number24
DOIs
Publication statusPublished - 2010 Dec 15

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Tumors
Breast Neoplasms
Neoplasm Metastasis
Sirolimus
Neoplasms
F-Box Proteins
CCAAT-Enhancer-Binding Proteins
Hypoxia-Inducible Factor 1
Proto-Oncogenes
Human Mammary Glands
Protein C
Tumor Suppressor Genes
Transgenic Mice
Proteolysis
Genes
Cells
Cell Survival
Inflammation
Hypoxia
Metabolism

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Balamurugan, K., Wang, J-M., Tsai, H. H., Sharan, S., Anver, M., Leighty, R., & Sterneck, E. (2010). The tumour suppressor C/EBPθ inhibits FBXW7 expression and promotes mammary tumour metastasis. EMBO Journal, 29(24), 4106-4117. https://doi.org/10.1038/emboj.2010.280
Balamurugan, Kuppusamy ; Wang, Ju-Ming ; Tsai, Hsin Hwa ; Sharan, Shikha ; Anver, Miriam ; Leighty, Robert ; Sterneck, Esta. / The tumour suppressor C/EBPθ inhibits FBXW7 expression and promotes mammary tumour metastasis. In: EMBO Journal. 2010 ; Vol. 29, No. 24. pp. 4106-4117.
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Balamurugan, K, Wang, J-M, Tsai, HH, Sharan, S, Anver, M, Leighty, R & Sterneck, E 2010, 'The tumour suppressor C/EBPθ inhibits FBXW7 expression and promotes mammary tumour metastasis', EMBO Journal, vol. 29, no. 24, pp. 4106-4117. https://doi.org/10.1038/emboj.2010.280

The tumour suppressor C/EBPθ inhibits FBXW7 expression and promotes mammary tumour metastasis. / Balamurugan, Kuppusamy; Wang, Ju-Ming; Tsai, Hsin Hwa; Sharan, Shikha; Anver, Miriam; Leighty, Robert; Sterneck, Esta.

In: EMBO Journal, Vol. 29, No. 24, 15.12.2010, p. 4106-4117.

Research output: Contribution to journalArticle

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