LMAN2 promotes breast cancer progression and deduces cell sensitivity to doxorubicin through stearoyl-CoA desaturase
TL;DR
LMAN2 is a robust prognostic biomarker that promotes breast tumor growth and anthracycline resistance by enabling SCD-dependent lipid desaturation and Therapeutic targeting of the LMAN2/SCD axis represents a promising strategy to overcome chemoresistance in breast cancer.
Abstract
Dysregulated lipid metabolism and chemoresistance are key drivers of breast cancer progression. Lectin, mannose-binding 2 (LMAN2) is frequently overexpressed in human breast tumors and functions as an oncogenic driver. However, whether LMAN2 contributes to chemoresistance remains unknown. We integrated multi-omics data from 1,085 primary tumors and matched normal tissues (from GEPIA and UALCAN) with functional studies in breast cancer cell lines and a doxorubicin (ADM)-treated nude mouse xenograft model. LMAN2 expression was modulated via siRNA/shRNA-mediated silencing or lentivirus-driven overexpression. Cellular phenotypes-including proliferation, migration, apoptosis, and response to ADM were systematically assessed. RNA-sequencing, untargeted lipidomics, and rescue experiments identified stearoyl-CoA desaturase (SCD) as a critical downstream effector. IC50 shifts and epistasis analysis further validated the role of the LMAN2/SCD axis in chemoresistance. LMAN2 mRNA was elevated across all molecular subtypes (luminal > HER2 > triple-negative) and predicted poorer overall survival (P = 5 × 10−4) and progression-free survival (P = 0.018). Silencing LMAN2 reduced clonogenicity by ~ 45% and migration by 37–63%, whereas overexpression increased cell viability by 1.4–1.7-fold and doubled motility. Knockdown of LMAN2 decreased the ADM IC50 by 4–5 fold, abolished macroscopic colony formation, and elevated apoptosis rates from 15 to 18% to 39–41%; these effects were reversed upon LMAN2 overexpression. In vivo, shLMAN2 combined with ADM reduced tumor volume and weight by 72% and 75%, respectively, compared to ADM alone (P < 0.001). Mechanistically, LMAN2 loss downregulated genes involved in “cholesterol homeostasis” and reduced total cellular cholesterol by 24%. SCD emerged as the most significantly downregulated enzyme and fully rescued the phenotypic and chemoresistance effects resulting from LMAN2 modulation. Epistasis experiments confirmed that LMAN2-mediated chemoresistance strictly depends on SCD function. LMAN2 is a robust prognostic biomarker that promotes breast tumor growth and anthracycline resistance by enabling SCD-dependent lipid desaturation. Therapeutic targeting of the LMAN2/SCD axis represents a promising strategy to overcome chemoresistance in breast cancer.