In silico disruption of TGF-β signalling in AR-deficient triple-negative breast cancer via AMP-based therapeutics

Triple-negative breast cancer (TNBC), an exceptionally aggressive type of breast cancer, accounts for 10–20% of cases worldwide and 31% of prevalent cases in India. TNBC lacks estrogen, progesterone, and HER2 receptors, rendering it resistant to traditional chemotherapy treatments. In AR-positive TNBC, androgen receptors (ARs) facilitate apoptosis and suppress cell proliferation; conversely, this therapeutic strategy is lacking in AR-negative TNBC. This study examines the efficacy of the antimicrobial peptides (AMPs) Plsa-07 and Plpl-18, which are derived from Lactobacillus spp., as targeted inhibitors of AR-negative TNBC. The in-vitro experiments demonstrated the impact of AR in three different breast cancer cell lines and revealedten key oncogenic drivers enriched in TGF-β signalling. The in silico experiments, such as Pancancer expression profiling, cancer hallmark analysis, and protein‒protein interaction network analysis emphasised the importance of THBS1 ( thbs1 ), SERPINE1 ( serpine1 ), and FN1 ( fn1 ), which are associated with pathways that facilitate epithelial‒mesenchymal transition and metastasis. Molecular docking revealed high-affinity binding of bothpeptides to the three possible targets, with a minimum binding free energy. Molecular dynamics simulations demonstratedleast RMSD fluctuations, and enhanced stability of peptide Plsa-07 association with SERPINE1. Overall, this study provides in silico evidence for the potential anti-proliferative effect of AMPs in AR-negative TNBC, supportingthe selective disruption of oncogenic protein targets within the TGF-β/Smad regulatory network. Thus, our study provides a basis for the design of AMP-based therapies to overcome resistance in molecularly defined subgroups of triple-negative breast cancer.