Master Regulators of Signaling Pathways: An Application to the Analysis of Gene Regulation in Breast Cancer

Tapia-Carrillo, Diana; Tovar, Hugo; Velázquez-Caldelas, Tadeo E.; Hernández‐Lemus, Enrique

doi:10.3389/fgene.2019.01180

Cited by 34 publications

(15 citation statements)

References 48 publications

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“…The overall observed depletion of pathways in mice agrees with our first case study. Moreover, the significant categories like vasculature development that are associated with morphogenesis, resemble an increased tumor burden of NeuT+ mice, which was previously confirmed with a large human RNA-seq dataset on breast cancer [39]. In both case studies we observed many associations with other types of cancers or diseases.…”

Section: Discussionsupporting

confidence: 78%

miEAA 2.0: Integrating multi-species microRNA enrichment analysis and workflow management systems

Kern

Fehlmann

Solomon

et al. 2020

Preprint

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AbstractGene set enrichment analysis has become one of the most frequently used applications in molecular biology research. Originally developed for gene sets, the same statistical principles are now available for all omics types. In 2016, we published the miRNA enrichment analysis and annotation tool (miEAA) for human precursor and mature miRNAs.Here, we present miEAA 2.0, supporting miRNA input from Homo sapiens, Mus musculus, and Rattus norvegicus. To facilitate inclusion of miEAA in workflow systems, we implemented an Application Programming Interface (API). Users can perform miRNA set enrichment analysis using either the web-interface, a dedicated Python package, or custom remote clients. Moreover, the number of category sets was raised by an order of magnitude. We implemented novel categories like annotation confidence level or localisation in biological compartments. In combination with the miR-Base miRNA-version and miRNA-to-precursor converters, miEAA supports research settings where older releases of miRBase are in use. The web server also offers novel comprehensive visualisations such as heatmaps and running sum curves with background distributions. Lastly, additional methods to correct for multiple hypothesis testing were implemented. We demonstrate the new features using case studies for human kidney cancer and mouse samples. The tool is freely accessible at: https://www.ccb.uni-saarland.de/mieaa2.

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Section: Discussionsupporting

confidence: 78%

miEAA 2.0: Integrating multi-species microRNA enrichment analysis and workflow management systems

Kern

Fehlmann

Solomon

et al. 2020

Preprint

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“…Interestingly, HOXB7 plays a role in DNA repair in addition to its function as transcriptional regulator [ 30 ]. MEIS2, which belongs to the same family of HOXB7, has been also reported to be a master regulator in breast cancer [ 31 ]. On the other hand, TCERG1 is involved in alternative splicing inhibiting the elongation of transcripts from target promoters by binding to RNA polymerase II, and has been identified as a regulator of proapoptotic proteins [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

MZ1 co-operates with trastuzumab in HER2 positive breast cancer

Noblejas-López

Nieto-Jiménez

Galán-Moya

et al. 2021

J Exp Clin Cancer Res

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Background Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context, novel drug combinations are needed to increase its antitumor activity. In this work, we have evaluated the efficacy of proteolysis targeting chimera (PROTAC) compounds based on BET inhibitors (BETi) to augment the activity of trastuzumab in HER2+ breast cancer models. Methods BT474 and SKBR3 HER2+ breast cancer cell lines were used. The effects of trastuzumab and the BET-PROTAC MZ1 either alone or in combination, were evaluated using MTT proliferation assays, three-dimensional invasion and adhesion cultures, flow cytometry, qPCR and Western blot. In vivo studies were carried out in a xenografted model in mice. Finally, a Clariom_S_Human transcriptomic array was applied to identify deregulated genes after treatments. Results MZ1 induced a higher antiproliferative effect compared to the BETi JQ1. The combination of MZ1 and -trastuzumab significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone. Evaluation of apoptosis resulted in an increase of cell death following treatment with the combination, and biochemical studies displayed modifications of apoptosis and DNA damage components. In vivo administration of agents alone or combined, to tumors orthotopically xenografted in mice, resulted in a decrease of the tumor volume only after MZ1-Trastuzumab combination treatment. Results from a transcriptomic array indicated a series of newly described transcription factors including HOXB7, MEIS2, TCERG1, and DNAJC2, that were associated to poor outcome in HER2+ breast cancer subtype and downregulated by the MZ1-trastuzumab combination. Conclusions We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development.

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“…While this study has given a broad perspective into key regulators of the immune response, further studies may adopt a similar approach to identify master regulators of specific immune pathways such as immune checkpoint interactions. Several methods and tools may facilitate identifying transcriptional regulators of signaling pathways and networks, such as MR4Cancer [42], iRegulon [92], and MARINa [93]. Here we listed some useful tools and their framework, which can be implemented to identify master regulators of ICs (Table 2).…”

Section: Approaches To Identify Potential Master Regulatorsmentioning

confidence: 99%

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

et al. 2020

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The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40–60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as “master regulators”, have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.

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Master Regulators of Signaling Pathways: An Application to the Analysis of Gene Regulation in Breast Cancer

Cited by 34 publications

References 48 publications

miEAA 2.0: Integrating multi-species microRNA enrichment analysis and workflow management systems

miEAA 2.0: Integrating multi-species microRNA enrichment analysis and workflow management systems

MZ1 co-operates with trastuzumab in HER2 positive breast cancer

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

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