Role of EMP2 and Del-1 in Tamoxifen-resistant Breast Cancer Cells.

BACKGROUND/AIM: Endocrine resistance remains a major clinical challenge in hormone receptor-positive (HR+) breast cancer. Although developmental endothelial locus-1 (Del-1) has been implicated in endocrine resistance, the regulatory pathways interacting with Del-1 remain poorly defined. This study aimed to identify molecular components associated with Del-1-driven resistance by performing RNA sequencing in tamoxifen-resistant (TAMR) breast cancer cells following Del-1 knockdown. MATERIALS AND METHODS: RNA sequencing was conducted in TAMR MCF-7 cells following Del-1 silencing to identify Del-1-regulated pathways in endocrine-resistant disease. Among the genes up-regulated after Del-1 suppression, epithelial membrane protein 2 (EMP2) was selected for further investigation due to its reported roles in cellular adhesion, metabolic signaling, and cancer stemness. Gene expression changes were validated using reverse transcription polymerase chain reaction (RT-PCR). Functional studies were performed using small interfering RNA (siRNA)-mediated knockdown of EMP2 or Del-1, followed by proliferation and clonogenic assays. RESULTS: Both EMP2 and Del-1 were up-regulated in luminal breast cancer cell lines. Suppression of Del-1 increased EMP2 expression in TAMR cells, consistent with RNA-seq findings. Notably, EMP2 suppression resulted in an increase in Del-1 expression, suggesting a potential regulatory feedback loop. Furthermore, knockdown of either Del-1 or EMP2 substantially enhanced colony formation in TAMR cells compared with controls. CONCLUSION: EMP2 may be involved in the regulation of Del-1 expression in TAMR breast cancer cells. Modulation of Del-1 or EMP2 influences cancer stemness in TAMR cells, underscoring the Del-1-EMP2 axis as a potential therapeutic target to overcome endocrine resistance.