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  • American Association for Cancer Research (AACR)  (13)
  • 1
    Online Resource
    Online Resource
    Hierarchical Phosphorylation of HOXB13 by mTOR Dictates Its Activity and Oncogenic Function in Prostate Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Research Vol. 21, No. 10 ( 2023-10-02), p. 1050-1063
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 10 ( 2023-10-02), p. 1050-1063
    Abstract: Dysregulation of mTOR signaling plays a critical role in promoting prostate cancer growth. HOXB13, a homeodomain transcription factor, is known to influence the androgen response and prostate cancer development. Recently, HOXB13 was found to complex with mTOR on chromatin. However, the functional crosstalk between HOXB13 and mTOR remains elusive. We now report that mTOR directly interacts with and hierarchically phosphorylates HOXB13 at threonine 8 and 41 then serine 31 to promote its interaction with the E3 ligase SKP2 while enhancing its oncogenic properties. Expression of HOXB13 harboring phosphomimetic mutations at the mTOR-targeted sites stimulates prostate cancer cellular growth both in vitro and in murine xenografts. Transcriptional profiling studies revealed a phospho-HOXB13–dependent gene signature capable of robustly discriminating between normal prostate tissues, primary and metastatic prostate cancer samples. This work uncovers a previously unanticipated molecular cascade by which mTOR directly phosphorylates HOXB13 to dictate a specific gene program with oncogenic implications in prostate cancer. Implications: Control of HOXB13 transcriptional activity via its direct phosphorylation by the mTOR kinase is a potential therapeutic avenue for the management of advanced prostate cancer.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-23-0086
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 2
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    Online Resource
    Androgen-Dependent Repression of ERRγ Reprograms Metabolism in Prostate Cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 2 ( 2017-01-15), p. 378-389
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 2 ( 2017-01-15), p. 378-389
    Abstract: How androgen signaling contributes to the oncometabolic state of prostate cancer remains unclear. Here, we show how the estrogen-related receptor γ (ERRγ) negatively controls mitochondrial respiration in prostate cancer cells. Sustained treatment of prostate cancer cells with androgens increased the activity of several metabolic pathways, including aerobic glycolysis, mitochondrial respiration, and lipid synthesis. An analysis of the intersection of gene expression, binding events, and motif analyses after androgen exposure identified a metabolic gene expression signature associated with the action of ERRγ. This metabolic state paralleled the loss of ERRγ expression. It occurred in both androgen-dependent and castration-resistant prostate cancer and was associated with cell proliferation. Clinically, we observed an inverse relationship between ERRγ expression and disease severity. These results illuminate a mechanism in which androgen-dependent repression of ERRγ reprograms prostate cancer cell metabolism to favor mitochondrial activity and cell proliferation. Furthermore, they rationalize strategies to reactivate ERRγ signaling as a generalized therapeutic approach to manage prostate cancer. Cancer Res; 77(2); 378–89. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-1204
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Abstract B46: Targeting EZH2 reactivates a breast cancer subtype-specific antimetastatic transcriptional program
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Research Vol. 16, No. 8_Supplement ( 2018-08-01), p. B46-B46
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 8_Supplement ( 2018-08-01), p. B46-B46
    Abstract: Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to the pathogenesis of many tumor types, including breast cancer. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. In this study, we demonstrate that genetic or pharmacologic targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behavior in a mouse model of breast cancer reflective of the luminal B subtype. We also employ patient-derived xenografts from different intrinsic subtypes of breast cancer to confirm that pharmacologic inhibition of Ezh2 activity hinders metastasis specifically in the luminal B subtype. We further define a molecular mechanism intrinsic to the luminal B subtype whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, antiinvasive transcriptional program. We demonstrate that higher FOXC1 levels are predictive of favorable outcome specifically in luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in luminal B breast cancer, where options for targeted therapy are currently limited. Citation Format: Alison Hirukawa, Harvey Smith, Dongmei Zou, Paul Savage, Radia Johnson, Guillaume Bourque, Vincent Giguere, Mark Basik, Cathy Dufour, Morag Park, William Muller. Targeting EZH2 reactivates a breast cancer subtype-specific antimetastatic transcriptional program [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B46.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.ADVBC17-B46
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2097884-4
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  • 4
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    Prostate Cancer Genetic-susceptibility Locus on Chromosome 20q13 is Amplified and Coupled to Androgen Receptor-regulation in Metastatic Tumors
    American Association for Cancer Research (AACR) ; 2014
    In:  Molecular Cancer Research Vol. 12, No. 2 ( 2014-02-01), p. 184-189
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 2 ( 2014-02-01), p. 184-189
    Abstract: The 20q13 chromosomal region has been previously identified as the hereditary prostate cancer genetic-susceptibility locus on chromosome 20 (HPC20). In this study, the 20q13 region was shown to be frequently co-amplified with the androgen receptor (AR) in metastatic prostate cancer. Furthermore, the AR signaling axis, which plays an essential role in the pathogenesis of prostate cancer, was demonstrated to be central to the regulation of the 20q13 common amplified region (CAR). High-resolution mapping analyses revealed hot spots of AR recruitment to response elements in the vicinity of most genes located on the 20q13 CAR. Moreover, amplification of AR significantly co-occurred with CAR amplification on 20q13 and it was confirmed that the majority of AR-bound genes on the 20q13 CAR were indeed regulated by androgens. These data reveal that amplification of the AR is tightly linked to amplification of the AR-regulated CAR region on 20q13. These results suggest that the cross-talk between gene amplification and gene transcription is an important step in the development of castration-resistant metastatic disease. Implications: These novel results are a noteworthy example of the cross-talk between gene amplification and gene transcription in the development of advanced prostate cancer. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/02/07/1541-7786.MCR-13-0477/F1.large.jpg. Mol Cancer Res; 12(2); 184–9. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-13-0477
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 5
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    Abstract 5253: Regulation of estrogen related receptor α by ING4 and its potential role in breast cancer pathogenesis
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5253-5253
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 5253-5253
    Abstract: Breast cancer is one of the most frequently diagnosed tumors in the United States that affects one in eight women during their lifetime. It is second only to lung cancer as cause of cancer death in women. The orphan members of the nuclear receptor superfamily, estrogen-related receptors ERRα and γ (ERRs) isoforms are considered the master regulators of energy metabolism and their transcriptional pathways are highly associated with the cancer phenotype. Realizing the important function of co-regulators on ERRs transcriptional activity and their impact on cancer development and progression, we have identified the tumor growth family member 4 (ING4), a protein that has been implicated in several solid tumors and physically interacts with ERRα in breast cancer cellular models and modulates its transcriptional activity. Examination of the Oncomine database revealed that both ING4 and ERRα gene expression were significantly higher in invasive ductal and lobular breast carcinomas compared to normal ones, and their increased expression is inversely correlated with the overall patient survival rate in The Cancer Genome Atlas (TCGA) database. Knocking down ING4 in a breast cancer cell line using siRNA technology significantly decreased the expression of ERRα, and overexpression of ING4 upregulates the endogenous expression of ERRα. Well-defined ERRα target genes were also regulated by ING4 in the same manner as ERRα. Also, depleting ING4 expression significantly increased breast cancer cell migration in in vitro scratch assays, while both ING4 and ERRα knockdown decreased breast cancer cell proliferation. Collectively, these findings provide evidence for positive regulation of ERRα by ING4. Understanding the mechanism by which ING4/ERRα interaction regulates cellular pathways in breast cancer, underscores the impact of such regulation on biological and pharmacological actions. Thus, they can be used for the development of improved novel pharmaceuticals that target ERRα/ING4 complex or its downstream pathways. Citation Format: Aymen A. Shatnawi, Vincent Giguere. Regulation of estrogen related receptor α by ING4 and its potential role in breast cancer pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5253.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-5253
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Genome-Wide Identification of Direct Target Genes Implicates Estrogen-Related Receptor α as a Determinant of Breast Cancer Heterogeneity
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 15 ( 2009-08-01), p. 6149-6157
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 15 ( 2009-08-01), p. 6149-6157
    Abstract: Estrogen-related receptor α (ERRα) is an orphan nuclear receptor, the expression of which correlates with negative prognosis in breast cancer. ERRα shares functional features with the estrogen receptor α (ERα) and its activity is modulated by the ERBB2 signaling pathway. Using genome-wide binding sites location analyses in ERα-positive and ERα-negative breast cancer cell lines, we show that ERRα and ERα display strict binding site specificity and maintain independent mechanisms of transcriptional activation. Nonetheless, ERRα and ERα coregulate a small subset of common target genes via binding either to a dual-specificity binding site or to distinct cognate binding sites located within the extended promoter region of the gene. Although ERRα signaling in breast cancer cells is mostly independent of ERα, the small fraction of common ERRα/ERα targets comprises genes with high relevance to breast tumor biology, including genes located within the ERBB2 amplicon and GATA3. Finally, unsupervised hierarchical clustering based on the expression profiling of ERRα direct target genes in human breast tumors revealed four main clusters that recapitulate established tumor subtypes. Taken together, the identification and functional characterization of the ERRα transcriptional network implicate ERRα signaling as a determinant of breast cancer heterogeneity. [Cancer Res 2009;69(15):6149–57]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-1251
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 7
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    Transcriptional Control of the ERBB2 Amplicon by ERRα and PGC-1β Promotes Mammary Gland Tumorigenesis
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 24 ( 2010-12-15), p. 10277-10287
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 24 ( 2010-12-15), p. 10277-10287
    Abstract: Overexpression of ERBB2 and its neighboring genes on chromosome 17 occurs in approximately 25% of breast tumors and is associated with poor prognosis. While amplification of the 17q12-21 chromosomal region often correlates with an increase in the transcriptional rates of the locus, the molecular mechanisms and the factors involved in the coordinated expression of genes residing within the ERBB2 amplicon remain largely unknown. Here we demonstrate that estrogen-related receptor α (ERRα, NR3B1) and its coregulator PGC-1β are key effectors in this process. Using a mouse model of ERBB2-initiated mammary tumorigenesis, we first show that ablation of ERRα significantly delays ERBB2-induced tumor development and lowers the levels of amplicon transcripts. Chromosome 17q-wide binding site location analyses in human breast cancer cells show preferential recruitment of ERRα to DNA segments associated with the ERBB2 amplicon. Furthermore, ERRα directs the co-recruitment of the coactivator PGC-1β to segments in the 17q12 region and the recruitment of RNA polymerase II to the promoters of the ERBB2 and coamplified genes. ERRα and PGC-1β also participate in the de-repression of ERBB2 expression through competitive genomic cross-talk with estrogen receptor α (ERα) and, as a consequence, influence tamoxifen sensitivity in breast cancer cells. Taken together, our results suggest that ERRα and PGC-1β are key players in the etiology of malignant breast cancer by coordinating the transcriptional regulation of genes located in the 17q12 region, a process that also involves interference with the repressive function of ERα on ERBB2 expression. Cancer Res; 70(24); 10277–87. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-2840
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    β-Catenin Signaling Is a Critical Event in ErbB2-Mediated Mammary Tumor Progression
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 14 ( 2013-07-15), p. 4474-4487
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 14 ( 2013-07-15), p. 4474-4487
    Abstract: Although ERBB2 amplification and overexpression is correlated with poor outcome in breast cancer, the molecular mechanisms underlying the aggressive nature of these tumors has not been fully elucidated. To investigate this further, we have used a transgenic mouse model of ErbB2-driven tumor progression (ErbB2KI model) that recapitulates clinically relevant events, including selective amplification of the core erbB2 amplicon. By comparing the transcriptional profiles of ErbB2KI mammary tumors and human ERBB2-positive breast cancers, we show that ErbB2KI tumors possess molecular features of the basal subtype of ERBB2-positive human breast cancer, including activation of canonical β-catenin signaling. Inhibition of β-catenin–dependent signaling in ErbB2KI-derived tumor cells using RNA interference impaired tumor initiation and metastasis. Furthermore, treatment of ErbB2KI or human ERBB2-overexpressing tumor cells with a selective β-catenin/CBP inhibitor significantly decreased proliferation and ErbB2 expression. Collectively, our data indicate that ERBB2-mediated breast cancer progression requires β-catenin signaling and can be therapeutically targeted by selective β-catenin/CBP inhibitors. Cancer Res; 73(14); 4474–87. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-3925
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    SREBF1 Activity Is Regulated by an AR/mTOR Nuclear Axis in Prostate Cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Research Vol. 16, No. 9 ( 2018-09-01), p. 1396-1405
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 9 ( 2018-09-01), p. 1396-1405
    Abstract: Reprogramming of cellular metabolism is an important feature of prostate cancer, including altered lipid metabolism. Recently, it was observed that the nuclear fraction of mTOR is essential for the androgen-mediated metabolic reprogramming of prostate cancer cells. Herein, it is demonstrated that the androgen receptor (AR) and mTOR bind to regulatory regions of sterol regulatory element-binding transcription factor 1 (SREBF1) to control its expression, whereas dual activation of these signaling pathways also promotes SREBF1 cleavage and its translocation to the nucleus. Consequently, SREBF1 recruitment to regulatory regions of its target genes is induced upon treatment with the synthetic androgen R1881, an effect abrogated upon inhibition of the mTOR signaling pathway. In turn, pharmacologic and genetic inhibition of SREBF1 activity impairs the androgen-mediated induction of the key lipogenic genes fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1). Consistent with these observations, the expression of the SREBF1, FASN, and SCD1 genes is significantly correlated in human prostate cancer tumor clinical specimens. Functionally, blockade of SREBF1 activity reduces the androgen-driven lipid accumulation. Interestingly, decreased triglyceride accumulation observed upon SREBF1 inhibition is paralleled by an increase in mitochondrial respiration, indicating a potential rewiring of citrate metabolism in prostate cancer cells. Altogether, these data define an AR/mTOR nuclear axis, in the context of prostate cancer, as a novel pathway regulating SREBF1 activity and citrate metabolism. Implications: The finding that an AR/mTOR complex promotes SREBF1 expression and activity enhances our understanding of the metabolic adaptation necessary for prostate cancer cell growth and suggests novel therapeutic approaches to target metabolic vulnerabilities in tumors. Mol Cancer Res; 16(9); 1396–405. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-17-0410
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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  • 10
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    Epidermal Growth Factor–Induced Signaling in Breast Cancer Cells Results in Selective Target Gene Activation by Orphan Nuclear Receptor Estrogen-Related Receptor α
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Research Vol. 65, No. 14 ( 2005-07-15), p. 6120-6129
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 14 ( 2005-07-15), p. 6120-6129
    Abstract: The orphan nuclear hormone receptor estrogen-related receptor α (ERRα, NR3B1) is a constitutive transcription factor that is structurally and functionally related to the classic estrogen receptors. ERRα can recognize both the estrogen response element and its own binding site (ERRE) in either dimeric or monomeric forms. ERRα is also a phosphoprotein whose expression in human breast tumors correlates with that of the receptor tyrosine kinase ErbB2, suggesting that its transcriptional activity could be regulated by signaling cascades. Here, we investigated growth factor regulation of ERRα function and found that it is phosphorylated in MCF-7 breast cancer cells in response to epidermal growth factor (EGF), an event that enhances its DNA binding. Interestingly, treatment with alkaline phosphatase shifts ERRα from a dimeric to a monomeric DNA-binding factor, and only the dimeric form interacts with the coactivator PGC-1α. In vitro, the DNA-binding domain of ERRα is selectively phosphorylated by protein kinase Cδ (PKCδ), which increases its DNA-binding activity, whereas expression of constitutively active PKCδ enhances TFF1 promoter activity via the ERRE. However, whereas treatment of MCF-7 cells with the phorbol ester phorbol-12-myristate 13-acetate also enhances ERRα activation of the TFF1 promoter reporter, it does not affect ERRα activity on its own promoter. In agreement, chromatin immunoprecipitation analysis shows that ERRα and RNA polymerase II are preferentially recruited to the TFF1 promoter after EGF treatment, whereas recruitment of these factors to its own promoter is not affected. These results reveal a mechanism through which growth factor signaling can selectively activate ERRα target genes in breast cancer cells.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-05-0922
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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