Regulatory role of tumor necrosis factor receptor-associated factor 6 in breast cancer by activating the protein kinase B/glycogen synthase kinase 3β signaling pathway

Mol Med Rep. 2017 Aug;16(2):2269-2273. doi: 10.3892/mmr.2017.6782. Epub 2017 Jun 15.

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an endogenous adaptor of innate and adaptive immune responses, and serves a crucial role in tumor necrosis factor receptor and toll‑like/interleukin‑1 receptor signaling. Although studies have demonstrated that TRAF6 has oncogenic activity, its potential contributions to breast cancer in human remains largely uninvestigated. The present study examined the expression levels and function of TRAF6 in breast carcinoma (n=32) and adjacent healthy (n=25) tissue samples. Compared with adjacent healthy tissues, TRAF6 protein expression levels were significantly upregulated in breast cancer tissues. Reverse transcription‑quantitative polymerase chain reaction analysis revealed a significant upregulation of the cellular proliferative marker Ki‑67 and proliferation cell nuclear antigen expression levels in breast carcinoma specimens. Furthermore, protein expression levels of the accessory molecule, transforming growth factor β‑activated kinase 1 (TAK1), were significantly increased in breast cancer patients, as detected by western blot analysis. As determined by MTT assay, TRAF6 exerted profoundly proliferative effects in the MCF‑7 breast cancer cell line; however, these detrimental effects were ameliorated by TAK1 inhibition. Notably, protein kinase B (AKT)/glycogen synthase kinase (GSK)3β phosphorylation levels were markedly upregulated in breast cancer samples, compared with adjacent healthy tissues. In conclusion, an altered TRAF6‑TAK1 axis and its corresponding downstream AKT/GSK3β signaling molecules may contribute to breast cancer progression. Therefore, TRAF6 may represent a potential therapeutic target for the treatment of breast cancer.

MeSH terms

  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Humans
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • Phosphorylation
  • Proliferating Cell Nuclear Antigen / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*
  • Up-Regulation

Substances

  • Ki-67 Antigen
  • Proliferating Cell Nuclear Antigen
  • TNF Receptor-Associated Factor 6
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7