Targeting Key Molecular Mechanisms in Triple-Negative Breast Cancer Therapies with Natural Compounds

Background: Triple-negative breast cancer (TNBC) is characterized by the absence of HER2 expression, progesterone receptor (PR), and estrogen receptor (ER). TNBC has a poor prognosis and limited therapy options due to its lack of specific targets and aggressive behavior. Aim: This review demonstrates the therapeutic efficacy and mechanisms of natural compounds in targeting key molecular pathways involved in the development and progression of TNBC, investigating their interaction with oncogenic signaling pathways. Methods: A thorough literature review was conducted using databases such as PubMed, Scopus, and Web of Science to identify studies assessing the anti-TNBC properties of natural compounds. Results: Natural bioactive compounds like curcumin, resveratrol, quercetin, EGCG, berberine, and thymoquinone have demonstrated promising anticancer properties in TNBC models. These limit metastasis, induce apoptosis, inhibit proliferation, and reverse chemoresistance by altering vital pathways like PI3K/AKT/ mTOR, MAPK/ERK, NF-κB, JAK/STAT, and Wnt/β-catenin. For example, quercetin inhibits NF-κB signalling and increases the cytotoxicity of doxorubicin, but curcumin decreases AKT phosphorylation. Furthermore, natural compounds may enhance immune response in BRCA-mutated TNBC by modifying immunological checkpoints, including PD-L1, when combined with PARP inhibitors. Conclusion: Natural compounds are a promising supplementary method for TNBC therapy due to their ability to target unregulated pathways and overcome therapeutic resistance. Nevertheless, challenges such as pharmacokinetics, limited bioavailability, and a lack of clinical validation persist. Future research should focus on combinatorial regimens, nanocarrier-based delivery technologies, and biomarker-guided clinical trials to develop successful TNBC treatments.