From dietary lignans to cancer therapy: Integrative systems analysis of enterolactone's molecular targets and signaling pathways in combatting cancer stem cells in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates. Cancer stem cells (CSCs) within TNBC contribute significantly to tumor progression, metastasis, and therapy resistance. This study explores Enterolactone (EL), a bioactive phenolic metabolite from dietary lignans, as a potential therapeutic agent against TNBC-CSCs. The investigation began by identifying potential therapeutic targets for EL against TNBC-CSCs using predictive databases. A PPI network was constructed in STRING to emphasize top hub targets. Insights were derived from mRNA expression patterns, tumor stage differentials, and survival analysis via UALCAN and GEPIA2. Molecular docking and dynamics simulations were carried out to explore EL's interactions with hub targets. GeneMANIA was employed to expand the target pool, generating two datasets. Preliminary FGN analysis and clustering of the second dataset were executed using GeneMANIA and MCODE plugins in CytoScape to enhance potential therapeutic avenues for EL against TNBC-CSCs. Employing network pharmacology, 53 potential EL targets against TNBC-CSCs were identified, highlighting the top 15 hub targets, including ESR1, AKT1, JUN, EGFR, and others. Functional analysis unveiled their involvement in critical pathways like PI3K/AKT/mTOR, Wnt-βcatenin, and MAPK, essential for CSC self-renewal, metastasis, and therapy resistance. GO and KEGG analyses illuminated the biological significance of these targets, elucidating EL's potential mechanisms. Analysis of GMFA-ED1 and -ED2 datasets expanded understanding, revealing novel targets of EL against TNBC-CSCs. In conclusion, EL demonstrates therapeutic potential against TNBC-CSCs by influencing crucial CSCs related molecular targets and Wnt-βcatenin and PI3K-AKT pathways, offering promising avenues in TNBC.