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

机译：LLGL2通过促进ER〜+乳腺癌中亮氨酸的摄取来缓解营养应激

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摘要

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 Drosophila(1), 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 treatment(4). However, the development of resistance to endocrine therapy and metastatic progression are leading causes of death for patients with ER+ disease(4). 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(5), and our findings identify an unexpected role for LLGL2 in this process.
机译：果蝇Lgl及其哺乳动物同源物LLGL1和LLGL2是调节上皮细胞顶基极性建立的支架蛋白（1,2）。 Lgl在果蝇中起着抑癌作用（1），而哺乳动物LLGL1和LLGL2在癌症中的作用尚不清楚。大多数乳腺癌（约75％）表达雌激素受体（ER）（3），患有这些肿瘤的患者接受内分泌治疗（4）。然而，对内分泌治疗的抵抗力的发展和转移进程是ER +病患者死亡的主要原因（4）。在这里我们报道，与LLGL1不同，LLGL2在ER +乳腺癌中过表达，并在营养胁迫下促进细胞增殖。 LLGL2通过与SLC7A5和膜融合蛋白YKT6形成三聚体复合物来调节亮氨酸转运蛋白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表达。乳腺癌细胞对内分泌治疗的耐药性与SLC7A5和LLGL2依赖于营养胁迫的适应性相关。 SLC7A5对赋予他莫昔芬治疗耐药性是必要和充分的，从而确定SLC7A5是克服乳腺癌对内分泌治疗耐药性的潜在治疗靶标。因此，LLGL2在ER +乳腺癌中起着肿瘤生长的促进剂的作用，而不是起抑癌作用。除乳腺癌外，适应营养压力至关重要（5），我们的发现确定了LLGL2在此过程中的出乎意料的作用。

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  • 来源
    《Nature》 |2019年第7755期|275-279|共5页
  • 作者

    Saito Yasuhiro; Li Lewyn; Coyaud Etienne; Luna Augustin; Sander Chris; Raught Brian; Asara John M.; Brown Myles; Muthuswamy Senthil K.;

  • 作者单位

    Harvard Med Sch, Dept Med, Canc Res Inst, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA|Harvard Med Sch, Dept Pathol, Canc Res Inst, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA|Keio Univ, Inst Adv Biosci, Yamagata, Japan;

    Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA|Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA;

    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada|Univ Toronto, Dept Med Biophys, Toronto, ON, Canada;

    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA;

    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada|Univ Toronto, Dept Med Biophys, Toronto, ON, Canada;

    Harvard Med Sch, Div Signal Transduct, Dept Med, Canc Res Inst,Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA;

    Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02115 USA|Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Med, Canc Res Inst, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA|Harvard Med Sch, Dept Pathol, Canc Res Inst, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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