New insights in gene expression alteration as effect of doxorubicin drug resistance in triple negative breast cancer cells

Ciocan-Cârtiţă, Cristina Alexandra; Jurj, Ancuța; Zănoagă, Oana; Cojocneanu, Roxana; Pop, Laura-Ancuta; Moldovan, Alin; Moldovan, Cristian; Zimța, Alina-Andreea; Ráduly, Lajos; Pop-Bica, Cecilia; Buse, Mihail; Budişan, Liviuţa; Virág, Piroska; Irimie, Alexandru; Dias, Sandra Martha Gomes; Braicu, Cornelia

doi:10.1186/s13046-020-01736-2

Cited by 21 publications

(14 citation statements)

References 36 publications

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“…Doxorubicin induces cell death and cell growth arrest primarily by inhibition of the topoisomerase II activity, DNA intercalation and production of free radicals, leading to apoptosis, autophagy, senescence and necrosis of the fast-growing cancer cells (Burgess et al, 2008;Meredith and Dass, 2016). In spite of the numerous genes, non-coding RNA and signaling pathways associated with doxorubicin resistance in breast cancer have been identified (Tormo et al, 2019;Ciocan-Cartita et al, 2020;Tanaka et al, 2020), the epigenetic regulatory mechanism, especially the role of chromatin-mediated processes in the regulation of gene expression, has not been investigated yet. Therefore, exploring the regulatory elements of doxorubicin-resistant genes and their corresponding transcription factors (TFs) in breast cancer is critically important for the elucidation of the disease process.…”

Section: Introductionmentioning

confidence: 99%

Integrated Chromatin Accessibility and Transcriptome Landscapes of Doxorubicin-Resistant Breast Cancer Cells

Wang

Yan

Shen

et al. 2021

Front. Cell Dev. Biol.

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BackgroundDoxorubicin is one of the most effective chemotherapeutic drugs for breast cancer while its common drug resistance leads to poor patient prognosis and survival. Growing evidence indicate dynamically reorganized chromatin allows rapid access of the gene regulatory machinery to open genomic regions facilitating subsequent gene expression through direct transcription factor (TF) activation and regulatory element binding.MethodsTo better understand the regulatory network underlying doxorubicin resistance in breast cancer cells, we explored the systematic alterations of chromatin accessibility and gene expression by the assay for transposase-accessible chromatin using sequencing (ATAC-seq) in combination with RNA sequencing, followed by integrative analysis to identify potential regulators and their targets associated with differentially accessible regions (DARs) in doxorubicin-resistant MCF7 (MCF7-DR) cells.ResultsA total of 3,963 differentially expressed genes (DEGs) related to doxorubicin resistance were identified, including dramatically up-regulated MT1E, GSTP1, LDHB, significantly down-regulated TFF1, UBB, DSCAM-AS1, and histone-modifying enzyme coding genes HDAC2, EZH2, PRMT5, etc. By integrating with transcriptomic datasets, we identified 18,228 DARs in MCF7-DR cells compared to control, which were positively correlated with their nearest DEGs (r = 0.6). There were 11,686 increased chromatin-accessible regions, which were enriched in up-regulated genes related to diverse KEGG pathways, such as the cell cycle, regulation of actin cytoskeleton, signaling pathways of MAPK, PI3K/Akt and Hippo, which play essential roles in regulating cell apoptosis, proliferation, metabolism, and inflammatory responses. The 6,542 decreased chromatin-accessible regions were identified for the declined doxorubicin-associated biological processes, for instance, endocrine and insulin resistance, central carbon metabolism, signaling pathways of TGF-beta and P53. Combining data from TCGA, analyses of the DAR sequences associated with the DNA-binding motifs of significantly enriched TF families including AP-1, TEAD and FOX, indicated that the loss-function of FOXA1 might play a critical role in doxorubicin-resistant breast cancer cells (DOX-R BCCs).ConclusionThese data exhibit the non-genetic landscape of chromatin accessibility and transcript levels in the DOX-R BCCs, and provide clear insights and resources for the detection of critical TFs and potential cis-regulatory elements-based putative therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

Integrated Chromatin Accessibility and Transcriptome Landscapes of Doxorubicin-Resistant Breast Cancer Cells

Wang

Yan

Shen

et al. 2021

Front. Cell Dev. Biol.

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“…6 . In addition, we aimed to compared the transcriptomic signature obtained with our compounds with previously published in relation to resistance to chemotherapy, as performed by other groups [ 22 ]. A gene drug resistance signature (NCBI, Accession: GPL1124) was compared with the down- and upregulated transcripts that we obtained after the administration of the different treatments (FC < -2, FC > 2, Supp.Fig.…”

Section: Resultsmentioning

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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“…DQ601914.1). We compiled a list of genes (CYP1A1, CYP1A2, ABCB1, GSTP1, MVP, EPHX1) 13 , RRM1 68 , RRM2 35 , (ABCC3, ABCC6, JUNB, CLU) 69 , (TOP2A, MCM4) 70 from previous studies on DOX resistance reported in different cancers such as breast cancer 13,69 , adrenocortical cancer 68 , pancreatic cancer 35 , and gastric cancer 70 . The complete mRNA sequence of these genes was retrieved from NCBI.…”

Section: Methodsmentioning

confidence: 99%

piR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair

2021

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Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown. PIWI-interacting RNAs (piRNAs) have been shown to enhance patient outcomes in cancers. However, there are few or no reports on piRNAs affecting chemotherapy in cancers, including fibrosarcoma. The current study aims to investigate the relationship between piR-39980 and DOX resistance and the underlying mechanisms. We reveal that piR-39980 is less expressed in DOX-resistant HT1080 (HT1080/DOX) fibrosarcoma cells. Our results show that inhibition of piR-39980 in parental HT1080 cells induces DOX resistance by attenuating intracellular DOX accumulation, DOX-induced apoptosis, and anti-proliferative effects. Its overexpression in HT1080/DOX cells, on the other hand, increases DOX sensitivity by promoting intracellular DOX accumulation, DNA damage, and apoptosis. The dual-luciferase reporter assay indicates that piR-39980 negatively regulates RRM2 and CYP1A2 via direct binding to their 3′UTRs. Furthermore, overexpressing RRM2 induces DOX resistance of HT1080 cells by rescuing DOX-induced DNA damage by promoting DNA repair, whereas CYP1A2 confers resistance by decreasing intracellular DOX accumulation, which piR-39980 restores. This study reveals that piR-39980 could reduce fibrosarcoma resistance to DOX by modulating RRM2 and CYP1A2, implying that piRNA can be used in combination with DOX.

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New insights in gene expression alteration as effect of doxorubicin drug resistance in triple negative breast cancer cells

Cited by 21 publications

References 36 publications

Integrated Chromatin Accessibility and Transcriptome Landscapes of Doxorubicin-Resistant Breast Cancer Cells

Integrated Chromatin Accessibility and Transcriptome Landscapes of Doxorubicin-Resistant Breast Cancer Cells

MZ1 co-operates with trastuzumab in HER2 positive breast cancer

piR-39980 mediates doxorubicin resistance in fibrosarcoma by regulating drug accumulation and DNA repair

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