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TRAF6 as a potential target in advanced breast cancer: a systematic review, meta-analysis, and bioinformatics
Feier Zeng1, Giovana Carrasco1, Boya Li1
1Department of Oncology and Metabolism, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
Abstract:
TRAF6 has emerged as a key regulator of breast cancer (BCa). However, the TRAF family constitutes of seven members that exhibit distinct and overlapping functions. To explore which TRAF represents a potential druggable target for BCa treatment, we searched Medline, Web of Science and Scopus for relevant studies from inception to June 27, 2021. We identified 14 in vitro, 11 in vivo and 4 human articles. A meta-analysis of pharmacological studies showed that in vitro inhibition of TRAF2/4 (mean difference (MD): - 57.49, 95% CI: - 66.95, - 48.02, P < 0.00001) or TRAF6 (standard(Std.)MD: - 4.01, 95% CI: - 5.75, - 2.27, P < 0.00001) is associated with reduction in BCa cell migration. Consistently, inhibition of TRAF2/4 (MD: - 51.08, 95% CI: - 64.23, - 37.94, P < 0.00001) and TRAF6 (Std.MD: - 2.80, 95% CI: - 4.26, - 1.34, P = 0.0002) is associated with reduced BCa cell invasion, whereas TRAF2/4 inhibition (MD: - 40.54, 95% CI: - 52.83, - 28.26, P < 0.00001) is associated with reduced BCa cell adhesion. Interestingly, only inhibition of TRAF6 (MD: - 21.46, 95% CI: - 30.40, - 12.51, P < 0.00001) is associated with reduced cell growth. In animal models of BCa, administration of pharmacological inhibitors of TRAF2/4 (Std.MD: - 3.36, 95% CI: - 4.53, - 2.18, P < 0.00001) or TRAF6 (Std.MD: - 4.15, 95% CI: - 6.06, - 2.24, P < 0.0001) in mice is associated with reduction in tumour burden. In contrast, TRAF6 inhibitors (MD: - 2.42, 95% CI: - 3.70, - 1.14, P = 0.0002) reduced BCa metastasis. In BCa patients, high expression of TRAF6 (Hazard Ratio: 1.01, CI: 1.01, 1.01, P < 0.00001) is associated with poor survival rate. Bioinformatics validation of clinical and pathway and process enrichment analysis in BCa patients confirmed that gain/amplification of TRAF6 is associated with secondary BCa in bone (P = 0.0079), and poor survival rate (P < 0.05). Overall, TRAF6 inhibitors show promise in the treatment of metastatic BCa. However, low study number and scarcity of evidence from animal and human studies may limit the translation of present findings into clinical practice.
Insights
Tumor necrosis factor receptor-associated factor 6 (TRAF6) inhibitors show promise for treating metastatic breast cancer (BCa). While TRAF2/4 and TRAF6 inhibition reduce BCa cell migration and invasion, only TRAF6 inhibition impacts BCa cell growth and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer (BCa) is a significant health concern, with the TRAF family of proteins playing a key role in its regulation.
- Understanding the specific roles of TRAF family members is crucial for identifying effective therapeutic targets in BCa treatment.
Approach:
- A comprehensive meta-analysis was conducted, searching Medline, Web of Science, and Scopus databases for studies on TRAF family members and BCa.
- The analysis included in vitro, in vivo, and human studies, focusing on the impact of TRAF inhibition on BCa cell migration, invasion, adhesion, and growth.
- Pharmacological studies investigated the effects of TRAF2/4 and TRAF6 inhibition on tumor burden and metastasis in animal models, alongside clinical data on TRAF6 expression and patient survival.
Key Points:
- In vitro inhibition of TRAF2/4 and TRAF6 significantly reduced BCa cell migration and invasion.
- TRAF6 inhibition uniquely decreased BCa cell growth and metastasis in vitro and in vivo.
- High TRAF6 expression in BCa patients correlated with poor survival rates and bone metastasis.
Conclusions:
- TRAF6 emerges as a critical regulator in breast cancer progression and metastasis.
- TRAF6 inhibitors demonstrate potential as a therapeutic strategy for metastatic breast cancer.
- Further research with larger study numbers and more extensive animal and human data is needed to translate these findings into clinical practice.
