LLGL2 Promotes Adaptation to Nutrient Stress in ER⁺ Breast Cancer

Resistance to endocrine therapy and metastatic progression is a leading cause of death in patients with estrogen receptor (ER)⁺ breast cancer. Saito and colleagues report that the scaffolding protein LLGL2, the human ortholog of a Drosophila tumor suppressor that regulates cell polarity, is overexpressed in ER⁺ breast cancer and promotes cellular proliferation under conditions of nutrient stress. High expression of LLGL2 was specific to ER⁺ breast cancer cell lines, breast cancer tissue samples, and patients with ER⁺/PR⁺ breast cancer, correlating with poor survival. In settings of nutrient stress, overexpression of LLGL2 promoted cell proliferation in vitro, and depletion of LLGL2 impaired proliferation in vitro and in vivo. Stimulation of ER⁺ breast cancer cells with estrogen induced expression of LLGL2 and restored proliferation under nutrient stress conditions, whereas deletion of an ER binding site within LLGL2 ablated these effects. Depletion of LLGL2 resulted in loss of multiple essential amino acids, but reintroduction of leucine rescued the proliferative defect observed in these cells. In response to nutrient stress, LLGL2 formed a trimeric complex with the leucine transport protein SLC7A5 and the SNARE protein YKT6 to stabilize SLC7A5 localization to the cell surface. Like LLGL2, high expression of SLC7A5 correlated with poor prognosis in patients with ER⁺/PR⁺ breast cancers, and depletion or pharmacologic inhibition of SLC7A5 impaired proliferation in vitro and in vivo. In patients with ER⁺ breast cancer who received tamoxifen treatment, high expression of LLGL2 and SLC7A5 correlated with poor survival. Tamoxifen-resistant cells expressed high levels of SLC7A5 and were insensitive to nutrient stress conditions, yet depletion of LLGL2 or inhibition of SLC7A5 was sufficient to restore sensitivity to tamoxifen under nutrient stress. Collectively, these data demonstrate that LLGL2 mediates cellular adaptation to nutritional stress and that SLC7A5 represents a potential therapeutic target to overcome endocrine resistance in breast cancer.

Saito Y, Li L, Coyaud E, Luna A, Sander C, Raught B, et al. LLGL2 rescues nutrient stress by promoting leucine uptake in ER⁺ breast cancer. Nature 2019;569:275–9.

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