Barua David, Abbasi Benazir, Gupta Ananya, Gupta Sanjeev
Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, National University of Ireland-Galway, Galway, Ireland.
Discipline of Physiology, Human Biology Building, School of Medicine, National University of Ireland-Galway, Galway, Ireland.
Heliyon. 2020 Oct 10;6(10):e05217. doi: 10.1016/j.heliyon.2020.e05217. eCollection 2020 Oct.
Somatic mutations of the estrogen receptor 1 gene (ESR1) is an emerging mechanism of acquired resistance to endocrine therapy in hormonal breast cancers. Hotspot point mutations in the ligand- binding domain of estrogen receptor α (ER) and genomic rearrangements producing ESR1 fusion genes are the two major types of mutations that are associated with endocrine resistance. The crosstalk between X-box binding protein 1 (XBP1), a key transcription factor of the unfolded protein response (UPR) and ER signalling creates a positive feedback loop that results in increased expression of XBP1 in ER-positive breast cancer. Here we report that XBP1 co-operated with point mutants (Y537S, D538G) and fusion mutants (ESR1-YAP1, ESR1-DAB2) of ESR1 to increase their transcriptional activity. XBP1 was required for optimal expression of estrogen-regulated genes, and up to 40% of XBP1-dependent genes were estrogen-responsive genes. Knockdown of XBP1 in genome-edited MCF7 cells expressing Y537S mutant reduced their growth, re-sensitized them to anti-estrogens and attenuated the constitutive and estrogen-stimulated expression of estrogen-regulated genes. Our study provides a rationale for overcoming endocrine resistance in breast cancers expressing ESR1 mutation by combining the XBP1 targeting agents with anti-estrogen agents.
雌激素受体1基因（ESR1）的体细胞突变是激素性乳腺癌获得性内分泌治疗耐药的一种新机制。雌激素受体α（ER）配体结合域的热点点突变和产生ESR1融合基因的基因组重排是与内分泌耐药相关的两种主要突变类型。未折叠蛋白反应（UPR）的关键转录因子X盒结合蛋白1（XBP1）与ER信号之间的相互作用形成了一个正反馈环，导致ER阳性乳腺癌中XBP1表达增加。在此我们报告，XBP1与ESR1的点突变体（Y537S、D538G）和融合突变体（ESR1-YAP1、ESR1-DAB2）协同作用，以增加它们的转录活性。XBP1是雌激素调节基因最佳表达所必需的，高达40%的XBP1依赖性基因是雌激素反应性基因。在表达Y537S突变体的基因组编辑MCF7细胞中敲低XBP1可降低其生长，使其重新对抗雌激素敏感，并减弱雌激素调节基因的组成型和雌激素刺激表达。我们的研究为通过将靶向XBP1的药物与抗雌激素药物联合使用来克服表达ESR1突变的乳腺癌的内分泌耐药提供了理论依据。
