Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis

Cell Death Dis. 2016 Dec 1;7(12):e2508. doi: 10.1038/cddis.2016.405.

Abstract

Transforming growth factor beta (TGFβ) signaling in breast cancer is selectively associated with pulmonary metastasis. However, the underlying mechanisms remain unclear. Here we show that Bcl-3, a member of the IκB family, serves as a critical regulator in TGFβ signaling to modulate breast cancer pulmonary metastasis. Bcl-3 expression was significantly associated with metastasis-free survival in breast cancer patients. Bcl-3 deletion inhibited the migration and invasion of breast cancer cells in vitro, as well as breast cancer lung metastasis in vivo. Bcl-3 was required for the expression of downstream TGFβ signaling genes that are involved in breast cancer lung metastasis. Bcl-3 knockdown enhanced the degradation of Smad3 but not Smad2 following TGFβ treatment. Bcl-3 could bind to Smad3 and prevent the ubiquitination and degradation of Smad3 protein. These results indicate that Bcl-3 serves as a promising target to prevent breast tumor lung metastasis.

MeSH terms

  • Animals
  • B-Cell Lymphoma 3 Protein
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Mice
  • Protein Stability
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction* / genetics
  • Smad3 Protein / metabolism*
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • B-Cell Lymphoma 3 Protein
  • BCL3 protein, human
  • Bcl3 protein, mouse
  • Proto-Oncogene Proteins
  • Smad3 Protein
  • Transcription Factors
  • Transforming Growth Factor beta