ESR1 fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes.
ESR1 fusion proteins invoke breast cancer subtype-dependent enrichment of ligand independent pro-oncogenic signatures and phenotypes.
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ESR1融合蛋白引起乳腺癌亚型依赖性配体独立的促癌特征和表型的富集。
DOI：
10.1101/2023.09.18.558175
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Oesterreich,Steffi
中科院分区：
文献类型：
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作者：
Yates,MeganE;Li,Zheqi;Li,Yiting;Guzolik,Hannah;Wang,Xiaosong;Liu,Tiantong;Hooda,Jagmohan;Atkinson,JenniferM;Lee,AdrianV;Oesterreich,Steffi
乳腺癌是女性死亡的主要原因，尽管在诊断和个性化治疗方面取得了进步，但由于耐药性，转移性疾病在很大程度上仍然无法治愈。幸运的是，对治疗耐药机制的识别迅速改变了我们对癌症逃避的理解，并使有针对性的治疗方案成为可能。当在三分之二的乳腺癌中表达的可药物雌激素受体(ER，ESR1)接受内分泌治疗时，大约30%的病例存在体细胞突变发展和随后的治疗耐药的风险。最近发现的ER介导内分泌耐药的一个新机制是ER融合蛋白的表达。ER融合保留了蛋白质的DNA结合域，HarborESR1外显子1-6与框架内基因伴侣融合，导致3‘ER配体结合域(LBD)的丢失。在这篇报告中，我们证明了在非特殊类型(NST)和浸润性小叶癌(ILC)细胞系模型中，ER融合蛋白表现出强大的典型ER信号通路的过度激活，而不依赖于配体雌二醇或抗内分泌治疗，如Fulvestrant和Tamoxifen。我们使用稳定过表达ER融合蛋白并同时下调内源性ER的细胞系模型，以最大限度地减少内源性野生型ER的影响。细胞系在已知是转移性疾病的驱动因素的途径中表现出共同的转录丰富，特别是MYC途径。异质的3‘融合伙伴，特别是转录因子SOX9和YAP1，引起不同程度的转录和转录活性，并转化为独特的表型读数。在此，我们报告了细胞系的活性是亚型、融合和检测特异性的，这表明LBD、3‘融合伙伴的缺失和细胞格局都影响融合活性。因此，根据肿瘤的临床病理特征，产生更多关于ER融合频率的数据将是至关重要的。有意义的ER融合蛋白在代表非特殊类型(NST)和浸润性小叶癌(ILC)亚型的乳腺癌细胞系中表现出不同的内分泌耐药机制。我们强调ER融合赋予的共享和独特的细胞适应能力，为进一步的翻译研究和临床决策提供了基础。
Breast cancer is a leading cause of female mortality and despite advancements in diagnostics and personalized therapeutics, metastatic disease largely remains incurable due to drug resistance. Fortunately, identification of mechanisms of therapeutic resistance have rapidly transformed our understanding of cancer evasion and is enabling targeted treatment regimens. When the druggable estrogen receptor (ER,ESR1), expressed in two-thirds of all breast cancer, is exposed to endocrine therapy, there is risk of somatic mutation development in approximately 30% of cases and subsequent treatment resistance. A more recently discovered mechanism of ER mediated endocrine resistance is the expression of ER fusion proteins. ER fusions, which retain the protein’s DNA binding domain, harborESR1exons 1-6 fused to an in-frame gene partner resulting in loss of the 3’ ER ligand binding domain (LBD). In this report we demonstrate that in no-special type (NST) and invasive lobular carcinoma (ILC) cell line models, ER fusion proteins exhibit robust hyperactivation of canonical ER signaling pathways independent of the ligand estradiol or anti-endocrine therapies such as Fulvestrant and Tamoxifen. We employ cell line models stably overexpressing ER fusion proteins with concurrent endogenous ER knockdown to minimize the influence of endogenous wildtype ER. Cell lines exhibited shared transcriptomic enrichment in pathways known to be drivers of metastatic disease, notably the MYC pathway. The heterogeneous 3’ fusion partners, particularly transcription factorsSOX9andYAP1, evoked varying degrees of transcriptomic and cistromic activity that translated into unique phenotypic readouts. Herein we report that cell line activity is subtype-, fusion-, and assay-specific suggesting that the loss of the LBD, the 3’ fusion partner, and the cellular landscape all influence fusion activity. Therefore, it will be critical to generate additional data on frequency of the ER fusions, in the context of the clinicopathological features of the tumor.SignificanceER fusion proteins exhibit diverse mechanisms of endocrine resistance in breast cancer cell lines representing the no special type (NST) and invasive lobular cancer (ILC) subtypes. Our emphasize upon both the shared and unique cellular adaptations imparted by ER fusions offers the foundation for further translational research and clinical decision making.