LLGL2 rescues nutrient stress by promoting leucine uptake in ER⁺ breast cancer

Drosophila Lgl and its mammalian homologues, LLGL1 and LLGL2, are scaffolding proteins that regulate the establishment of apical-basal polarity in epithelial cells^1,2. Whereas Lgl functions as a tumour suppressor in Drosophila¹, the roles of mammalian LLGL1 and LLGL2 in cancer are unclear. The majority (about 75%) of breast cancers express oestrogen receptors (ERs)³, and patients with these tumours receive endocrine treatment⁴. However, the development of resistance to endocrine therapy and metastatic progression are leading causes of death for patients with ER⁺ disease⁴. Here we report that, unlike LLGL1, LLGL2 is overexpressed in ER⁺ breast cancer and promotes cell proliferation under nutrient stress. LLGL2 regulates cell surface levels of a leucine transporter, SLC7A5, by forming a trimeric complex with SLC7A5 and a regulator of membrane fusion, YKT6, to promote leucine uptake and cell proliferation. The oestrogen receptor targets LLGL2 expression. Resistance to endocrine treatment in breast cancer cells was associated with SLC7A5- and LLGL2-dependent adaption to nutrient stress. SLC7A5 was necessary and sufficient to confer resistance to tamoxifen treatment, identifying SLC7A5 as a potential therapeutic target for overcoming resistance to endocrine treatments in breast cancer. Thus, LLGL2 functions as a promoter of tumour growth and not as a tumour suppressor in ER⁺ breast cancer. Beyond breast cancer, adaptation to nutrient stress is critically important⁵, and our findings identify an unexpected role for LLGL2 in this process.