PCO26-270: Transcriptomic Profiling Reveals Inflammatory and Epithelial-Mesenchymal Transition Pathway Activation in Endoxifen-Resistant Estrogen Receptor-Positive Breast Cancer

Background: (Z)-Endoxifen, the active metabolite of tamoxifen, demonstrates superior anti-estrogenic activity and favorable tolerability in estrogen receptor–positive (ER+) breast cancer. While clinically promising, mechanisms of resistance to endoxifen remain poorly characterized, limiting its broader clinical utility and precision therapeutic delivery. Objective: To elucidate transcriptomic alterations underlying acquired endoxifen resistance in ER+ breast cancer cells and identify potential predictive biomarkers and novel therapeutic targets. Methods: RNA sequencing datasets from endoxifen-sensitive and endoxifen-resistant MCF7 breast cancer cell models were analyzed using the PandaOmics artificial intelligence platform. Differential gene expression and pathway enrichment analyses compared molecular signatures. Correlation and intersection analyses identified shared and unique features of resistance. Results: Endoxifen-resistant cells showed deeper suppression of estrogen response genes and retention of some antiproliferative signaling compared with sensitive cells. Resistance was associated with marked upregulation of proinflammatory signaling (tumor necrosis factor alpha/nuclear factor kappa B, interferon alpha/gamma), epithelial-mesenchymal transition, and mechanistic target of rapamycin complex 1 signaling—hallmarks unchanged or suppressed in sensitive cells. Protein kinase C beta (PRKCB), a known target of endoxifen, was specifically elevated in resistant cells, suggesting adaptive reprogramming. Over 8,000 genes were uniquely dysregulated in resistant cells, approximately 2,700 in sensitive cells, and approximately 3,800 were shared between phenotypes. A subset of mechanistic target of rapamycin complex 1 pathway genes was downregulated in sensitive but upregulated in resistant cells. Conclusions: Endoxifen resistance involves transcriptional rewiring characterized by sustained estrogen pathway suppression, activation of inflammatory and epithelial-mesenchymal transition programs, and reversal of mechanistic target of rapamycin complex 1 pathway regulation. These changes highlight candidate biomarkers (e.g., PRKCB, IFI44, CXCL8) and therapeutic vulnerabilities, supporting strategies that incorporate immune-inflammatory and epithelial-mesenchymal transition modulators for managing resistant ER+ breast cancer.