Lethal giant larvae homolog 2 (LLGL2) (LLGL2)

Lethal giant larvae homolog 2 (LLGL2) is a scaffolding protein primarily involved in the establishment and maintenance of apical-basal cell polarity in epithelial tissues (UniProt Q6P1M3). While its homologs often function as tumor suppressors, LLGL2 has been identified as a critical survival factor in estrogen receptor-positive (ER+) breast cancer, where it is frequently overexpressed (Saito et al., 2019, Nature). In these malignant contexts, LLGL2 facilitates the recruitment of the leucine transporter SLC7A5 (LAT1) to the plasma membrane, enabling cancer cells to overcome nutrient stress and proliferate under low-nutrient conditions (Saito et al., 2019). This metabolic adaptation makes LLGL2 mRNA a promising therapeutic target, as its depletion can selectively induce proteotoxic stress and inhibit tumor growth in ER+ breast cancer models (PubMed: 31316201). Currently, therapeutic approaches are largely experimental, focusing on the use of RNA interference (RNAi) or antisense oligonucleotides to downregulate LLGL2 expression (Nature, 2019). Targeting LLGL2 represents a strategy to disrupt the metabolic plasticity of cancer cells, potentially providing a synergistic effect when combined with existing endocrine therapies (NCBI Gene: 1536).

Other names

LGL2Hugl-2HGLHuman giant larvae homolog 2Lethal(2) giant larvae protein homolog 2

Targeting LLGL2 mRNA via RNA interference (RNAi) or antisense technology leads to the degradation of the transcript, preventing the translation of the LLGL2 protein. This loss of LLGL2 protein disrupts the trafficking of the SLC7A5 (LAT1) leucine transporter to the cell surface, thereby starving cancer cells of essential amino acids and inhibiting tumor growth (Saito et al., 2019).