LLGL2 (Lethal giant larvae homolog 2) is a scaffolding protein that regulates epithelial cell polarity and serves context-dependent roles in cancer. In normal physiology, LLGL2 functions as part of a polarity complex involved in spindle orientation and epithelial apical-basal polarity establishment 1. However, LLGL2 exhibits divergent functions across cancer types. In estrogen receptor-positive (ER+) breast cancer, LLGL2 is overexpressed and promotes tumor growth by forming a trimeric complex with the leucine transporter SLC7A5 and YKT6 to enhance leucine uptake under nutrient stress, facilitating endocrine therapy resistance 12. Conversely, in colorectal cancer, LLGL2 functions as a tumor suppressor by stabilizing THBS3 mRNA through interaction with CNOT1, thereby inactivating the PI3K-Akt pathway; MDM2-mediated LLGL2 degradation promotes cancer progression 3. In prostate cancer, LLGL2 knockdown induces autophagy and reverses epithelial-mesenchymal transition by upregulating E-cadherin while suppressing pro-EMT markers 4. LLGL2 shows differential cytoplasmic expression in prostatic ductal adenocarcinoma and may serve as a diagnostic biomarker in latent tuberculosis infection 56. These findings establish LLGL2 as a context-dependent regulator with therapeutic implications across multiple malignancies.