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Transcriptome analysis of ovaries by subcutaneous injections of olaparib in wild-type and BRCA1+/- rats.

ABSTRACT: BRCA1 pathogenic variant may have the negative impact on ovarian function. Poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor, olaparib exploit the principle of synthetic lethality to selectively kill the cells that have a deficiency in homologous recombination repair. To evaluate the effect to olaparib on ovaries, we performed the study of subcutaneous olaparib injections for 2 weeks in wild-type and BRCA1+/- rats. We compared the microarray gene expression profiles of rat ovary tissues from the study.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE249187 | GEO | 2025/02/15

REPOSITORIES: GEO

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Olaparib based photo-affinity probes for PARP-1 detection in living cells

Project description:The poly-ADP-ribose polymerase (PARP) is a protein from the family of ADP-ribosyltransferases that catalyzes poly adenosine diphosphate ribose (ADPR) formation in order to attract the DNA repair machinery to DNA damage sites. Inhibition of PARP activity by olaparib can cause cell death which is of clinical relevance in some tumor types. This demonstrates that quantification of PARP activity in the context of living cells is of great importance. In this work we present the design, synthesis and biological evaluation of photo-activatable affinity probes inspired by the olaparib molecule which are equipped with a diazirine for covalent attachment upon activation by UV light and a ligation handle for the addition of a reporter group of choice. SDS-PAGE, western blotting and label-free LC-MS/MS quantification analysis show that the probes target the PARP-1 protein and are selectively outcompeted by olaparib suggesting binding in the same enzymatic pocket.

2020-04-29 | PXD018661 | Pride

Genome-wide analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells

Project description:Analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells. The hypothesis tested in the present study was that enzalutamide influences the expression of genes that are involved in important bioprocesses in prostate cance rcells, including DNA damage response genes and this effect may synergize with poly(ADP-ribose) polymerase inhibitor olaparib in cytotoxicity to prstate cancer cells. prostate cancer cells were pretreated with enzalutamide or vehicle control DMSO for 24 h, followed by treatment with enzalutamide, olaparib, enzalutamide+olaparib, or vehicle control DMSO for 48 h. Gene expression in enzalutamide+olaparib-treated cells was compared with taht in vehicle control- and single agent-treated cells.

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Olaparib resistance and cisplatin responses in triple negative breast cancer

Project description:PARP inhibitor and platinum based drugs such as cisplatin are promising therapies for triple negative breast cancer and exploit the deficiencies in BRCA1 or BRCA2, or homologous recombination repair defects. However, PARP inhibitor resistance is proven to be a major clinical problem. Acquired PARP inhibitor resistance has been linked with co-resistance to platinum-based drugs. To determine how acquired olaparib resistance affects cisplatin response and whether this is influenced by their BRCA1 status, we performed RNAseq transcriptome analysis of isogenic triple negative breast cancer models of olaparib resistance with normal and mutant BRCA1.

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Olaparib

Project description:Olaparib

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PARP inhibition elicits STING-dependent antitumor immune responses in Brca1-deficient ovarian cancer

Project description:To examine the immune responses that occur in Brca1-deficent tumors upon olaparib treatment, we performed gene expression analysis of a panel of 4604 cancer and immune-related genes in tumor tissues harvested from Brca1-deficient ovarian tumor-bearing mice after treatment with olaparib or vehicle. Transcriptome analysis showed that the expression of genes associated with immune response, T-cell activation and interferon-gamma(IFNgamma) response were markedly upregulated in tumors treated with olaparib as compared to vehicle. Our data reveal the antitumor immune response of PARP inhibition and demonstrate that it contributes to therapeutic efficacy of PARP inhibition in Brca1-deficient tumors.

2019-02-13 | GSE120500 | GEO

Genome-wide analysis of enzalutamide- and/or olaparib-responsive gene expression in prostate cancer cells

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Transcriptome Analysis of Gene Expression involving C/EBPβ and Olaparib Resistance

Project description:Poly(ADP-ribose) polymerase inhibitors (PARPi) are now widely used in treating ovarian cancer. However, PARPi resistance emerges gradually. To investigate the change of gene expression during the transition, we have induced a stable resistant cell strain by culturing A2780 in the continued presence of olaparib. We then performed RNA-seq of the resistant strain and its parent line A2780. We found that C/EBPβ was strongly correlated with PARPi resistance. RNA-seq of C13* after C/EBPβ knockdown was also performed.

2021-05-15 | GSE153867 | GEO

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis.

Project description:Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway, and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial and most efforts aimed to identify BRCA1/BARD1 ubiquitination substrates rely on indirect evidence. Here, we observed that the BRCA1/BARD1 ubiquitin E3 activity was not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identified substrates for BRCA1/BARD1. PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18, avoiding the formation of ssDNA gaps during DNA replication and promoting replication fork stability upon replication stress, solving the controversy about the function of BRCA1/BARD1 E3 activity in Homologous Recombination.

2024-05-07 | PXD039167 | Pride

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis.

Project description:Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway, and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial and most efforts aimed to identify BRCA1/BARD1 ubiquitination substrates rely on indirect evidence. Here, we observed that the BRCA1/BARD1 ubiquitin E3 activity was not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identified substrates for BRCA1/BARD1. We found that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results address the controversy about the function of BRCA1/BARD1 E3 activity in Homologous Recombination.

2024-05-07 | PXD050319 | Pride

Blocking Fra-1 sensitizes triple-negative breast cancer to olaparib

Project description:Fra-1 (FOSL1) is overexpressed in triple-negative breast cancer (TNBC). Fra-1 is a member of the activator protein 1 (AP-1) transcription factor complex, which plays crucial roles in tumor progression and treatment resistance. We have previously identified 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells in a large screen, and these included PARP1(Poly (ADP-ribose) polymerase 1). PARP1 inhibitor olaparib is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that this interaction impacts the efficacy of olaparib treatment. We corroborate that PARP1 interacts with Fra-1, and we show that PARP1 downregulates Fra-1 and consequently reduces AP-1 transcriptional activity. Inhibition of PARP1, on the other hand, increases Fra-1 levels and enhances its transcriptional activity, which in turn can increase treatment resistance. However, by inhibiting Fra-1, we found that TNBC cells became sensitized to olaparib treatment. We compared Fra-1 chromatin binding sites with the Fra-1 and PARP1 regulated transcriptomes, and found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We further show that PARP1 protein levels significantly correlate with Fra-1 in clinical breast cancer tumors, and we identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall, but not in basal-like tumors. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a therapeutic approach to improve olaparib treatment outcome for TNBC patients.

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