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N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer

ABSTRACT: N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer

PROVIDER: PRJNA855952 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19987600.fastq.gz	Fastqsanger.gz
	SRR19988900_1.fastq.gz	Fastqsanger.gz
	SRR19988900_2.fastq.gz	Fastqsanger.gz
	SRR19987601.fastq.gz	Fastqsanger.gz
	SRR19989001_1.fastq.gz	Fastqsanger.gz

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N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [RNAseq_WAP]

Project description:N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [RNAseq_WAP]

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N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [ATAC-seq]

Project description:N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [ATAC-seq]

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N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer.

Project description:Breast cancer is the second most common cancer type worldwide, representing 25% of all cancers in women. PIK3CA is one of the most frequently mutated genes in breast cancer and mutations result in constitutive activation of the PI3K/mTOR pathway. More than 30 inhibitors against PI3K/mTOR are being tested in clinical trials, however, resistance mechanisms evolve frequently resulting in disease progression. The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. For this purpose, we used a genome-wide PiggyBac transposon mediated mutagenesis screen in a PIK3CAH1047R mutated murine tumor model. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. Additionally, we find that loss of NF1 correlates with enhanced glycolysis and lower levels of ROS. Unexpectedly, treatment with NAC sensitized NF1 KO cells to PI3K inhibition in vitro, and in vivo. Global phospho-proteomics indicated that the combination with NAC enhances the inhibitory effect of PI3K inhibition on mTOR signaling, which inhibits proliferation of NF1 KO tumor cells. This raises the interesting possibility to combine PI3K inhibition with NAC especially in NF1 loss tumors

2023-03-30 | PXD034644 | Pride

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [T47D RNA-seq]

Project description:N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [T47D RNA-seq]

| PRJNA855956 | ENA

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [RNAseq_WAP]

Project description:The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. By looking at differentially expressed genes we wanted to investigate the effect of NF1 KO in T47D cells and if they respond differentially to BYL719 compared to the T47D CTRL cells.

2023-03-16 | GSE207512 | GEO

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [ATAC-seq]

2023-03-16 | GSE207513 | GEO

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [T47D RNA-seq]

2023-03-16 | GSE207514 | GEO

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-16 | GSE207515 | GEO

Transcription profiling of human NF1 heterozygous (NF1+/-) melanocytes from a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient

Project description:One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where dysregulation of melanocyte development, proliferation and differentiation is considered to play a key etiopathogenic role. To gain better insight in the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented and hyperpigmented lesional café-au-lait skin. Out of 13,850 unique genes, a total of 137 had a significant twofold or more up- (72) or down-regulated (65) expression in NF1+/- melanocytes compared to NF1+/+ melanocytes (genotype effect). Considering possible intrinsic genetic variation in lesional skin, melanocytes showed a total of 51 genes having a significant twofold or more up- (37) or down-regulated (14) expression when they were cultured from hyperpigmentary café-au-lait skin compared to normally pigmented skin (lesional skin type effect). NF1+/- café-au-lait skin melanocytes showed 468 genes with a significant two-fold or more up- (183) or down-regulated (285) expression going beyond the sum of the separate main effects (interaction). Detailed analysis enabled the identification of several modulated genes in NF1+/- (café-au-lait skin) melanocytes, mainly involved in controlling cell proliferation and cell maintenance, in cell adhesion and, surprisingly, in the immune response. An interesting finding was that a high number of transcription factor genes were differentially modulated, among which a specific subset - important in melanocyte-lineage development - showed downregulation in a transcriptional cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.

2005-02-05 | E-MEXP-258 | biostudies-arrayexpress

Nf1 deletion and recurrent copy number alterations in mammary tumorigenesis

Project description:Breast cancer is the most prevalent cancer in women, and most cases are believed to have a sporadic, rather than heritable basis. Therefore, a major challenge in cancer research is to determine the underlying genomic alterations leading to carcinogenesis and malignancy, and then use this information for personalized therapies. Genomic studies of human cancers that aim to identify causative mutations are complicated by the prevalence of passenger mutations, genetic heterogeneity, and the diversity of breast cancer etiologies and tumor subtypes. Mouse cancer models are powerful for untangling the genomic basis of cancers because genetic and phenotypic variation can be eliminated or controlled. To identify genes contributing to mammary tumorigenesis, we exploited the C3H-Mcm4Chaos3/Chaos3 (“Chaos3”) mouse model that, by virtue of bearing a defective DNA replicative helicase subunit that causes elevated genomic instability (GIN), sustains somatic alterations ultimately causing mammary adenocarcinomas. Genomic analysis of Chaos3 mammary tumors revealed recurrent copy number alterations (CNAs) of specific genomic regions, most notably deletion of the Neurofibromin 1 (Nf1) tumor suppressor gene in all cases. NF1, a negative regulator of RAS, is traditionally recognized for its role in driving the development of neurofibromas in the context of the human disease Neurofibromitosis but not breast cancer. We observed elevated RAS activation and increased sensitivity of both Chaos3 and human Nf1-mutated breast cancer lines to MAPK and/or PI3K/AKT pathway inhibitors. We also found striking overlap between Chaos3 CNAs and human breast cancer CNA data curated in public genomic databases, including Nf1 deletion. Together, our results indicate that spontaneous NF1 loss can drive breast cancer and suggests a potential therapeutic strategy in that subset of patients. reference x sample

2012-08-21 | E-GEOD-36240 | biostudies-arrayexpress

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