PO.EN01.01 · 内分泌肿瘤
内分泌耐药性乳腺癌中ATAD2的治疗性靶向
Therapeutic targeting of ATAD2 in endocrine-resistant breast cancer
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摘要 Abstract
中文摘要
引言：ATPase家族AAA结构域蛋白2（ATAD2）是一种高度保守的蛋白，作为致癌转录因子的共激活因子发挥功能，其溴结构域对其与乙酰化染色质的结合至关重要。ATAD2在包括乳腺癌在内的多种癌症类型中频繁扩增。ATAD2的上调常与不良患者结局相关，可用作预后标志物。在乳腺癌中，ATAD2被认为作为雌激素受体（ER）α的共激活因子，在雌二醇刺激时被选择性募集，导致一部分ER靶基因（包括c-Myc、cyclin D1和E2F1）的诱导，这些基因是乳腺癌细胞增殖所必需的。在此，我们研究了ATAD2在携带ESR1激活突变的激素耐药转移性ER阳性乳腺癌中的作用，此类癌症目前治疗选择有限。
方法：我们检测了ATAD2在人乳腺肿瘤及亚型特异性乳腺癌细胞（包括内分泌治疗耐药乳腺癌细胞）中的表达。为研究ATAD2在Y537S和D538G突变乳腺癌细胞中的治疗潜力，我们对内分泌耐药乳腺癌细胞进行了ATAD2的遗传学和药理学调控。此外，我们在Y537S突变的MCF-7和T47D细胞中使用shRNA建立了ATAD2的稳定抑制。我们还进行了共免疫沉淀实验，证明了ATAD2与ERalpha在Y537S MCF-7细胞中的相互作用。
结果：对癌症基因组图谱（TCGA）和临床蛋白质组肿瘤分析联盟（CPTAC）数据集的分析显示，与正常乳腺组织相比，ATAD2的mRNA和蛋白水平在所有主要亚型中均升高。此外，ATAD2在内分泌耐药乳腺癌细胞中过表达，包括Y537S帕博西尼（palbociclib）耐药和长期雌激素剥夺（LTED）细胞系模型。ATAD2的药理学和siRNA介导的抑制显著降低了Y537S和D538G突变乳腺癌细胞中ERalpha及其靶基因的表达。更重要的是，通过遗传学或药理学手段抑制ATAD2可有效阻断内分泌耐药乳腺癌细胞中配体依赖性和配体非依赖性的ER信号传导。最后，我们的共免疫沉淀实验显示ERalpha直接与ATAD2相互作用。
结论：总体而言，我们的研究强调ATAD2是内分泌耐药乳腺癌中ESR1突变信号传导所必需的。因此，阻断ATAD2是一种针对内分泌耐药乳腺癌（包括ESR1突变乳腺癌）的有前景的治疗策略。
查看英文原文 English abstract
Introduction: ATPase family AAA domain-containing protein 2 (ATAD2) is a highly conserved protein that functions as a coactivator of oncogenic transcription factors, and its bromodomain is critical for its association with acetylated chromatin. ATAD2 is frequently amplified in multiple types of cancer, including breast cancer. The upregulation of ATAD2 is often associated with poor patient outcomes and can be used as a prognostic marker. In breast cancer, ATAD2 is proposed to act as a coactivator of estrogen receptor (ER) alpha, which is selectively recruited upon estradiol stimulation, leading to the induction of a subset of ER target genes, including c-Myc, cyclin D1, and E2F1, which are required for breast cancer cell proliferation. Here, we examined the role of ATAD2 in hormone-resistant metastatic ER-positive breast cancers with activating mutations in ESR1, which currently have limited therapeutic options.
Methods: We examined the expression of ATAD2 in human breast tumors and subtype-specific breast cancer cells, including endocrine therapy-resistant breast cancer cells. To investigate the therapeutic potential of ATAD2 in Y537S and D538G mutant breast cancer cells, we conducted genetic and pharmacological modulation of ATAD2 in endocrine-resistant breast cancer cells. Additionally, we established stable suppression of ATAD2 using shRNA in the Y537S mutant MCF-7 and T47D cells. We also performed a co-immunoprecipitation assay, which demonstrated an interaction between ATAD2 and ERalpha in Y537S MCF-7 cells.
Results: Analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) data sets revealed elevated mRNA and protein levels of ATAD2 across all major subtypes compared with normal breast tissues. Additionally, ATAD2 was overexpressed in endocrine-resistant breast cancer cells, including Y537S palbociclib resistance and long-term estrogen-deprived (LTED) cell line models. Pharmacological and siRNA-mediated inhibition of ATAD2 significantly reduced the expression of ERalpha and its target genes in Y537S and D538G mutant breast cancer cells. More importantly, the inhibition of ATAD2 by a genetic or pharmacological agent potentially blocks ligand-dependent and ligand-independent ER signaling in endocrine-resistant breast cancer cells. Finally, our co-immunoprecipitation experiments showed that ERalpha directly interacts with ATAD2.
Conclusion: Collectively, our study highlights that ATAD2 is necessary for ESR1 mutant signaling in endocrine-resistant breast cancer. Therefore, blocking ATAD2 is a promising therapeutic strategy for endocrine-resistant breast cancer, including ESR1 mutant breast cancer.
利益披露 Disclosure
A. Devakrishnan, None..
M. Palaniappan, None.