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NF-κB Is a Potential Molecular Drug Target in Triple-Negative Breast Cancers
Paola Poma1, Manuela Labbozzetta1, Natale D'Alessandro1
1Pharmacology Unit, Department of Health Sciences and Mother and Child Care "G. D'Alessandro," School of Medicine, University of Palermo , Palermo, Italy .
Abstract:
Breast cancer continues to cause significant burden in global health morbidity and mortality. Triple-negative breast cancers (TNBCs) are highly aggressive with poor prognosis and are characterized by lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (Her-2). TNBCs are often resistant to cytotoxic chemotherapy and pose major difficulty in achieving personalized medicine due to their molecular heterogeneity. There is increasing evidence that the aberrant activation of nuclear factor (NF)-κB signaling is a frequent characteristic of TNBCs. We evaluated the effects of different potential NF-κB inhibitors, such as bisindolylmaleimide I (BIS, a selective protein kinase C [PKC] inhibitor), MG132 (a proteasome inhibitor), curcumin (endowed with pleiotropic activities), and dehydroxymethylepoxyquinomicin (an inhibitor of NF-κB translocation into the nucleus) on the constitutive activation of NF-κB present in three TNBC cell lines (SUM 149, SUM 159, and MDA-MB-231). We also evaluated whether MDA-9/Syntenin plays a role in NF-κB activation, as observed in other cancer types. Indeed, silencing experiments with a siRNA anti-MDA-9/Syntenin produced a very strong reduction of NF-κB activation in all the three TNBC cell lines. We conclude that different approaches targeting NF-κB activation might potentially prove useful for innovation in anticancer drug development for TNBCs. Further research that bridge preclinical and clinical investigations with NF-κB inhibitors would be timely and warranted.
Insights
Targeting nuclear factor kappa B (NF-κB) signaling pathways shows promise for treating aggressive triple-negative breast cancers (TNBCs). Inhibiting NF-κB activation, potentially via MDA-9/Syntenin, offers new avenues for TNBC drug development.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis, often resistant to standard therapies.
- Aberrant activation of nuclear factor kappa B (NF-κB) signaling is frequently observed in TNBCs.
- Molecular heterogeneity of TNBCs presents challenges for personalized medicine and effective treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of various NF-κB inhibitors in triple-negative breast cancer cell lines.
- To investigate the role of MDA-9/Syntenin in NF-κB activation within TNBC.
- To explore novel therapeutic strategies for TNBC by targeting NF-κB signaling.
Main Methods:
- Utilized three TNBC cell lines (SUM 149, SUM 159, MDA-MB-231) to assess NF-κB activation.
- Tested inhibitors including bisindolylmaleimide I (PKC inhibitor), MG132 (proteasome inhibitor), curcumin, and dehydroxymethylepoxyquinomicin.
- Performed silencing experiments using siRNA against MDA-9/Syntenin to determine its role in NF-κB activation.
Main Results:
- Constitutive NF-κB activation was observed in all three TNBC cell lines.
- Several NF-κB inhibitors demonstrated effects on NF-κB activation.
- Silencing MDA-9/Syntenin significantly reduced NF-κB activation across all tested TNBC cell lines.
Conclusions:
- Targeting NF-κB activation presents a potential therapeutic strategy for triple-negative breast cancer.
- MDA-9/Syntenin plays a role in NF-κB activation in TNBC, suggesting it as a potential therapeutic target.
- Further research integrating preclinical and clinical studies on NF-κB inhibitors is warranted for TNBC drug development.