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

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

PROVIDER: PRJNA1047624 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2025-02-15 | GSE249187 | GEO

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.

2021-07-22 | GSE165914 | GEO

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

A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer

Project description:A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer

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A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer

Project description:A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated (BRCA1/2m) metastatic breast cancer

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Multi-omics characterization of acquired Olaparib resistance in BRCA1 and BRCA2 mutant breast cancer cell lines

Project description:Poly (ADP-ribose) polymerase inhibitors (PARPi) are widely used as targeted therapies against breast cancers with BRCA mutations. However, the development of resistance to PARPi poses a significant challenge for these therapies, warranting further need for mechanistic insight into PARPi resitance. Here, we generate and characterize Olaparib resistant (OR) clones of BRCA1/2 mutant breast cancer cell lines MDAMB436 and HCC1428 using a systems-level multi-omics approach, including transcriptome, proteome, phosphoproteome and ADP-ribosylation analysis. Our analyses revealed that resistance development was most strongly driven by protein changes, with modest effects on phosphorylation- and ADP-ribosylation-dependent signaling pathways. We found that BRCA1 expression was reestablished in all OR MDAMB436 clones, whereas PARP1 expression was decreased. In OR HCC1428 clones, BRCA2 function was not restored. However, we saw increased expression of Fanconi anemia group D2 (FANCD2), HPF1 and Nicotinamide phosphoribosyltransferase (NAMPT) in various OR clones, suggesting increased replication fork protection, changes in the ADPr pathway and adaptation of metabolic pathways as a resistance mechanism. Our findings provide valuable insights into the complex landscape of PARPi resistance, offering potential targets for further investigation and therapeutic intervention.

2025-08-25 | PXD060950 | Pride

Multi-omics characterization of acquired Olaparib resistance in BRCA1 and BRCA2 mutant breast cancer cell lines

Project description:This is part 2 of the same project. Part 1 was just uploaded with the reference: 1-20250110-174238-3123982. Please merge if possible! Poly (ADP-ribose) polymerase inhibitors (PARPi) are widely used as targeted therapies against breast cancers with BRCA mutations. However, the development of resistance to PARPi poses a significant challenge for these therapies, warranting further need for mechanistic insight into PARPi resitance. Here, we generate and characterize Olaparib resistant (OR) clones of BRCA1/2 mutant breast cancer cell lines MDAMB436 and HCC1428 using a systems-level multi-omics approach, including transcriptome, proteome, phosphoproteome and ADP-ribosylation analysis. Our analyses revealed that resistance development was most strongly driven by protein changes, with modest effects on phosphorylation- and ADP-ribosylation-dependent signaling pathways. We found that BRCA1 expression was reestablished in all OR MDAMB436 clones, whereas PARP1 expression was decreased. In OR HCC1428 clones, BRCA2 function was not restored. However, we saw increased expression of Fanconi anemia group D2 (FANCD2), HPF1 and Nicotinamide phosphoribosyltransferase (NAMPT) in various OR clones, suggesting increased replication fork protection, changes in the ADPr pathway and adaptation of metabolic pathways as a resistance mechanism. Our findings provide valuable insights into the complex landscape of PARPi resistance, offering potential targets for further investigation and therapeutic intervention.

2025-08-25 | PXD060046 | 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.

2016-07-03 | E-GEOD-69249 | biostudies-arrayexpress

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

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