Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors

Whately, Kristina Marinak; Voronkova, Maria A.; Maskey, Abha; Gandhi, Jasleen; Loskutov, Juergen; Choi, Hyung Soon; Yanardag, Sila; Chen, Dongquan; Wen, Sijin; Margaryan, Naira V.; Smolkin, Matthew B.; Purazo, Marc L.; Hu, Gangqing; Pugacheva, Elena N.

doi:10.1038/s41388-021-01969-1

Cited by 16 publications

(19 citation statements)

References 44 publications

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“…In addition, the integrated function of all the different sequence elements is not known and constitutes a fundamental research quest of a complete framework of AURKA transcriptional regulation. It is also important to note the recurring phenomenon in which transcription of AURKA is regulated by some factors that AURKA engages with in protein-protein interactions, such as p53 [86], HIF1 [87], EGFR [88], Myc and FOXM1 [7] (figure 1). This suggests the presence of uncharted regulatory feedback loops, the exploration of which may reveal integrative circuits that control critical cellular functions, in addition to being exploited for therapeutic purposes [89,90].…”

Section: Transcriptional Regulationmentioning

confidence: 99%

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

Cacioppo

Lindon

2022

Open Biol.

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Aurora Kinase A (AURKA) is a positive regulator of mitosis with a strict cell cycle-dependent expression pattern. Recently, novel oncogenic roles of AURKA have been uncovered that are independent of the kinase activity and act within multiple signalling pathways, including cell proliferation, survival and cancer stem cell phenotypes. For this, cellular abundance of AURKA protein is per se crucial and must be tightly fine-tuned. Indeed, AURKA is found overexpressed in different cancers, typically as a result of gene amplification or enhanced transcription. It has however become clear that impaired processing, decay and translation of AURKA mRNA can also offer the basis for altered AURKA levels. Accordingly, the involvement of gene expression mechanisms controlling AURKA expression in human diseases is increasingly recognized and calls for much more research. Here, we explore and create an integrated view of the molecular processes regulating AURKA expression at the level of transcription, post-transcription and translation, intercalating discussion on how impaired regulation underlies disease. Given that targeting AURKA levels might affect more functions compared to inhibiting the kinase activity, deeper understanding of its gene expression may aid the design of alternative and therapeutically more successful ways of suppressing the AURKA oncogene.

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Section: Transcriptional Regulationmentioning

confidence: 99%

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

Cacioppo

Lindon

2022

Open Biol.

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“…We screened 21 upregulated differential genes and 43 downregulated differential genes by comparing drug-resistant BC tissues with normal BC tissues. We performed functional enrichment analysis of these differential genes and GO analysis showed that most genes were enriched in cancer-related functions, such as negative regulation of apoptosis (Thrane et al, 2015), cellular response to hypoxia (Whately et al, 2021), and protein homogenization activity (Skidmore et al, Frontiers in Cell and Developmental Biology frontiersin.org 2020); these processes were also closely associated with drug resistance in BC. In the KEGG analysis, differential genes were mostly enriched in metabolic pathways and cancer-related pathways (Erdelyi et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen resistance-related ceRNA network for breast cancer

Qiao

Lei²,

Zhang³

et al. 2022

Front. Cell Dev. Biol.

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Background: Tamoxifen (TMX) is one of the most widely used drugs to treat breast cancer (BC). However, acquired drug resistance is still a major obstacle to its application, rendering it crucial to explore the mechanisms of TMX resistance in BC. This aims of this study were to identify the mechanisms of TMX resistance and construct ceRNA regulatory networks in breast cancer.Methods: GEO2R was used to screen for differentially expressed mRNAs (DEmRNAs) leading to drug resistance in BC cells. MiRTarbase and miRNet were used to predict miRNAs and lncRNAs upstream, and the competing endogenous RNA (ceRNA) regulatory network of BC cell resistance was constructed by starBase. We used the Kaplan–Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) to analyze the expression and prognostic differences of genes in the ceRNA network with core axis, and qRT-PCR was used to further verify the above conclusions.Results: We found that 21 DEmRNAs were upregulated and 43 DEmRNA downregulated in drug-resistant BC cells. DEmRNAs were noticeably enriched in pathways relevant to cancer. We then constructed a protein-protein interaction (PPI) network based on the STRING database and defined 10 top-ranked hub genes among the upregulated and downregulated DEmRNAs. The 20 DEmRNAs were predicted to obtain 113 upstream miRNAs and 501 lncRNAs. Among them, 7 mRNAs, 22 lncRNAs, and 11 miRNAs were used to structure the ceRNA regulatory network of drug resistance in BC cells. 4 mRNAs, 4 lncRNAs, and 3 miRNAs were detected by GEPIA and the Kaplan–Meier plotter to be significantly associated with BC expression and prognosis. The differential expression of the genes in BC cells was confirmed by qRT-PCR.Conclusion: The ceRNA regulatory network of TMX-resistant BC was successfully constructed and confirmed. This will provide an important resource for finding therapeutic targets for TMX resistance, where the discovery of candidate conventional mechanisms can aid clinical decision-making. In addition, this resource will help discover the mechanisms behind this type of resistance.

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“…The Cancer Genome Atlas (TCGA, https://www.cancer.gov) breast cancer data and Kaplan-Meier Plotter (https://kmplot.com) web-based tools were used to evaluate genomic DNA and RNA-seq expression of NEDD9 in HER2+ breast cancer as previously described [31,32]. The specific selection criteria used for analysis provided in Supplementary Figure 1.…”

Section: Tumor Micro Array and Patient Datamentioning

confidence: 99%

“…All chemicals, BSA and buffers were purchased from Fisher Scientific, Pittsburgh, PA, USA. Antigen retrieval was performed using citrate buffer, pH 8.0 at 98C, for 20 minutes as previously reported [34]. Sections were subsequently blocked using 5% Bovine Serum Albumin (BSA), 1xTBS solution.…”

Section: Fluorescent Immunohistochemistry and Hematoxylin And Eosin (...mentioning

confidence: 99%

NEDD9 Overexpression Causes Hyperproliferation of Luminal Cells and Cooperates with HER2 Oncogene in Tumor Initiation: A Novel Prognostic Marker in Breast Cancer

Purazo¹,

Ice²,

Shimpi³

et al. 2023

Preprint

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The HER2 overexpression occurs in 10–20% of breast cancer patients. HER2+ tumors are characterized by increase in Ki67, early relapse and increased metastasis. There is little known about factors influencing early stages of HER2- tumorigenesis and diagnostic markers. Previously, it was shown that deletion of NEDD9 in mouse models of HER2 cancer interferes with tumor growth, but the role of NEDD9 upregulation is currently unexplored. We report that NEDD9 is overexpressed in a significant subset of HER2+ breast cancers and correlates with limited response to anti-HER2 therapy. To investigate the mechanisms through which NEDD9 influences HER2-dependent tumorigenesis, we generated MMTV-Cre-NEDD9 transgenic mice. The analysis of mammary glands shows extensive ductal epithelium hyperplasia, increased branching, and terminal end bud expansion. The addition of oncogene Erbb2 (neu) leads to development of early hyperplastic benign lesions earlier (~16 weeks) with a significantly shorter latency than the control mice. Similarly, NEDD9 upregulation in MCF10A-derived acini leads to hyperplasia like DCIS. This phenotype is associated with activation of ERK1/2 and AURKA kinases leading to an increased proliferation of luminal cells. These findings indicate that NEDD9 is setting permissive conditions for HER2-induced tumorigenesis, thus identifying this protein as a potential diagnostic marker for early detection.

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Nuclear Aurora-A kinase-induced hypoxia signaling drives early dissemination and metastasis in breast cancer: implications for detection of metastatic tumors

Cited by 16 publications

References 44 publications

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

Regulating the regulator: a survey of mechanisms from transcription to translation controlling expression of mammalian cell cycle kinase Aurora A

Tamoxifen resistance-related ceRNA network for breast cancer

NEDD9 Overexpression Causes Hyperproliferation of Luminal Cells and Cooperates with HER2 Oncogene in Tumor Initiation: A Novel Prognostic Marker in Breast Cancer

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