MLK4 kinase regulates the DNA damage response and promotes triple-negative breast cancer chemoresistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA731126 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14585600_1.fastq.gz | Fastqsanger.gz | |||
| SRR14585600_2.fastq.gz | Fastqsanger.gz | |||
| SRR14585603_1.fastq.gz | Fastqsanger.gz | |||
| SRR14585603_2.fastq.gz | Fastqsanger.gz | |||
| SRR14585604_1.fastq.gz | Fastqsanger.gz |
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Project description:Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen and progesterone receptors, and the lack of HER2 amplification or overexpression. Chemoresistance is currently one of the major challenges in the treatment TNBC. Therefore, there is a need towards identification of the novel molecular targets that could be exploited to overcome TNBC chemoresistance. In this study, we found that knock-down of Mixed-Lineage Kinase 4 (MLK4), a member of MAP3K family of serine/threonine kinases, sensitizes TNBC cell to chemotherapy and impairs activation of DNA repair pathways upon genotoxic treatment. DNA damage response signaling network coordinates transcriptional response at multiple levels to preserve cellular homeostasis and promote survival in response to genotoxic stress. Since MLK4-deficient cells were compromised for DNA damage response signaling activation following doxorubicin treatment, we hypothesized that the loss of MLK4 could significantly affect global transcriptomic changes induced by chemotherapy in TNBC cells. To test this hypothesis we performed gene expression profiling by mRNA-seq in HCC1806 TNBC cells transfected with control or MLK4-targeting siRNAs and treated with either 1 μM of doxorubicin for 24 h or vehicle only (DMSO control). Our RNA-seq analysis revealed that MLK4 is required for DNA damage-induced expression of several NF-кB-associated cytokines, including IL-6, which facilitates TNBC cells survival in an autocrine manner.
2021-11-28 | GSE174692 | GEO
Project description:Transcriptomic profiling was applied to investigate the effects of polo-like kinase 1 inhibition in triple-negative breast cancer.
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Project description:This SuperSeries is composed of the following subset Series: GSE21719: Identification of the receptor tyrosine kinase AXL in triple negative breast cancer as a novel target for the human miR-34a microRNA (miRNA study) GSE21832: Identification of the receptor tyrosine kinase AXL in triple negative breast cancer as a novel target for the human miR-34a microRNA (gene expression) Refer to individual Series
2010-12-31 | E-GEOD-21834 | biostudies-arrayexpress
Project description:Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, triple-negative is the subtype that lacks the expression of major differentiation markers (i.e. estrogen receptor [ER]), ant its high cellular plasticity results in higher aggressiveness and poor prognosis compared to other subtypes. Whether plasticity poses a vulnerability to cancer cells remains elusive. Here, we show that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer. Using a high-throughput reporter drug screen with 9,501 compounds, we identify three polo-like kinase 1 (PLK1) inhibitors as major inducers of ER protein expression and downstream activity in triple-negative breast cancer cells via the transcription factor BATF. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest and ultimately cell death. Notably, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line and patient-derived xenograft models. In addition, genes upregulated upon PLK1 inhibition are correlated with expression in normal breast tissue and confer better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition might be an alternative strategy to treat triple-negative breast cancer.
2022-08-23 | PXD028495 | Pride
Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer. Expression microarrays in H3K27ac in triple-negative breast cancer +/- treatment with covalent CDK7 inhibitor THZ1 treatment
2015-09-24 | E-GEOD-69106 | biostudies-arrayexpress
Project description:<p>In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer.</p> <p>Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC.</p> <p>In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.</p>
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Project description:NEK2 is a mitotic kinase that is upregulated and mislocalized in the nucleus of human cancer cells. NEK2 modulates expression and activity of both transcription and splicing factors in cancer cells, nevertheless whether this kinase affects transcriptome regulation genome widely and whether this activity concurs to its oncogenic activity is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 cells transiently silenced for NEK2 we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this kinase.
2021-12-21 | GSE140803 | GEO
Project description:Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is a mind aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Gene set enrichment analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy.
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Project description:The aim of this study was evaluate the transcriptome changes in the comparison between triple negative tumors with increased SPARC expression and triple negative tumors with decreased SPARC expression according to Nagai et al., 2011 (Breast Cancer Res Treat (2011) 126:1–14) The results generated could be of particular interest to better define the prognostic impact of SPARC expression in triple negative breast tumors
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Project description:About 15-20% of all breast cancers are triple negative breast cancers, which are often highly aggressive. We performed global quantitative phosphotyrosine profiling of a large panel of triple negative breast cancer cell lines using high resolution Fourier transform mass spectrometry. Our study identified 1,903 tyrosine-phosphorylated peptides derived from 969 proteins. Heterogeneous activation of tyrosine kinases was observed in triple negative breast cancer derived cell lines.
2016-07-06 | PXD001222 | Pride