Department of Medicine, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Nature. 2019 May;569(7755):275-279. doi: 10.1038/s41586-019-1126-2. Epub 2019 Apr 17.
Drosophila Lgl and its mammalian homologues, LLGL1 and LLGL2, are scaffolding proteins that regulate the establishment of apical-basal polarity in epithelial cells. Whereas Lgl functions as a tumour suppressor in Drosophila, the roles of mammalian LLGL1 and LLGL2 in cancer are unclear. The majority (about 75%) of breast cancers express oestrogen receptors (ERs), and patients with these tumours receive endocrine treatment. However, the development of resistance to endocrine therapy and metastatic progression are leading causes of death for patients with ER disease. 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 important, and our findings identify an unexpected role for LLGL2 in this process.
果蝇 Lgl 及其哺乳动物同源物 LLGL1 和 LLGL2 是调节上皮细胞顶底极性建立的支架蛋白。虽然 Lgl 在果蝇中作为肿瘤抑制因子发挥作用，但哺乳动物 LLGL1 和 LLGL2 在癌症中的作用尚不清楚。大多数（约 75%）乳腺癌表达雌激素受体（ERs），这些肿瘤患者接受内分泌治疗。然而，对内分泌治疗的耐药性和转移进展的发展是 ER 疾病患者死亡的主要原因。在这里，我们报告说，与 LLGL1 不同，LLGL2 在 ER 乳腺癌中过表达，并在营养应激下促进细胞增殖。LLGL2 通过与 SLC7A5 和膜融合调节剂 YKT6 形成三聚体复合物来调节 SLC7A5 的细胞表面水平，从而促进亮氨酸摄取和细胞增殖。雌激素受体靶向 LLGL2 的表达。乳腺癌细胞对内分泌治疗的耐药性与 SLC7A5 和 LLGL2 依赖性适应营养应激有关。SLC7A5 是赋予他莫昔芬治疗耐药性所必需的，这表明 SLC7A5 是克服乳腺癌内分泌治疗耐药性的潜在治疗靶点。因此，LLGL2 在 ER 乳腺癌中作为肿瘤生长的促进因子而不是肿瘤抑制因子发挥作用。除了乳腺癌，适应营养应激至关重要，我们的发现确定了 LLGL2 在这一过程中的意外作用。
