Genomic landscape of BRCA1-deficient tumors upon PARPi treatment
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ABSTRACT:
PROVIDER: PRJEB25799 | ENA |
REPOSITORIES: ENA
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Project description:Genomic landscape of BRCA1-deficient tumors upon PARPi treatment
| PRJEB25803 | ENA
Project description:The aim of the study is to identify differences in the global phosphoproteome across a BRCA1-deficient mouse mammary tumor panel. We have matched PARPi-naive and PARPi-resistant tumors, in which resistance was induced in vivo (mice bearing tumors were treated with PARPi untill the tumors stopped responding). Each pair of matched naive/resistant tumors originate from a different original tumor donor (one can consider each individual donor as an individual patient). From another analysis (RAD51 IRIF) we know that the mechanism of PARPi-resistance in a number of the tumors is driven by alterations in DNA damage response. Therefore, we can divide the tumors into four groups: (A) HR proficient, the exact mechanism not known, (B) HR proficient due to the loss of 53bp1 (TP53BP1), (C) HR proficient due to loss of Rev7 (MAD2L2) and (D) HR deficient, mechanism of resistance not known. Additionally, each tumor from our panel was retransplanted and challenged with 15 Gy irradiation to trigger a DNA damage response, therefore for each tumor we have an irradiated (IR) and a non-irradiated (NIR) sample. In this experiment each sample was processed in duplicate. Given all this, group (A) consists of 6 individual donors x 2 (matched naive/resistant) x 2 (NIR/IR) x 2 (duplicate) = 48 samples (samples 1-48); groups (B)-(D): 2 donors (per group) x 2 (naive/resistant) x 2 (NIR/IR) x 2 (duplicate) = 16 samples/group (B: samples 65-80, C: samples 81-96 and D: 49-64, according to the OPL label). In total this gives: 48 + 16 +16 +16 = 96 samples. Part of this analysis is used in the paper that also describes data from PXD031711
2022-06-06 | PXD032007 | Pride
Project description:RNAseq of Brca1-deficient mouse mammary tumors
| PRJNA625044 | ENA
Project description:Understanding BRCA1 function in INK4-RB deficient tumors
| PRJNA655906 | ENA
Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie RNA sequencing.
2021-11-17 | GSE148565 | GEO
Project description:The use of poly(ADP-ribose) polymerase inhibitors (PARPi) has proven largely successful in targeting BRCA1/2-mutated tumours. However, the emergence of PARPi-resistant disease can reduce the efficacy of this treatment, posing significant challenges in the clinic. Here, we use multiple models of BRCA1-/- cells and patient-derived xenografts (PDXs) that have been treated with PARPi until they no longer respond to the drug, to characterise genomic and transcriptomic alterations specific to PARPi resistance. We find that abrogation of TP53BP1 expression occurs spontaneously during prolonged PARPi treatment and is caused by genomic deletions and promoter methylation. Moreover, genes upregulated in PARPi-resistant cells and tumours predominantly consist of innate immune response genes, including ISG15 and factors of the ISGylation machinery. We demonstrate that ISG15 inhibition re-sensitises PARPi-resistant cells to the drug exogenous and, conversely, that ISG15 overexpression in BRCA1-/- cells triggers PARPi resistance. Mechanistically, ISG15 is required in BRCA1-/- PARPi-resistant cells for replication fork progression and for DNA double-strand break (DSB) repair via homologous recombination (HR). Our results indicate that complex ISG15 interactions with DNA replication/repair factors can drive PARPi resistance in BRCA1-deficient cancer cells and that targeting ISG15 has the potential to overcome PARPi resistance.
2026-08-18 | PXD069001 | Pride
Project description:The use of poly(ADP-ribose) polymerase inhibitors (PARPi) has proven largely successful in targeting BRCA1/2-mutated tumours. However, the emergence of PARPi-resistant disease can reduce the efficacy of this treatment, posing significant challenges in the clinic. Here, we use multiple models of BRCA1-/- cells and patient-derived xenografts (PDXs) that have been treated with PARPi until they no longer responded to the drug, to characterise genomic and transcriptomic alterations specific to PARPi resistance. We find that abrogation of TP53BP1 expression occurs spontaneously during prolonged PARPi treatment, alongside TP53BP1 genomic deletions and promoter methylation. Additionally, innate immune response genes, including ISG15 and factors of the ISGylation machinery are upregulated in PARPi-resistant cells and tumours. We demonstrate that ISG15 inhibition re-sensitises PARPi-resistant cells to the drug and, conversely, that ISG15 overexpression in BRCA1-/- cells promotes PARPi resistance. Mechanistically, BRCA1-/- PARPi-resistant cells rely on ISG15 for replication fork progression and restart of stalled forks and for DNA double-strand break (DSB) repair via homologous recombination (HR). Our results indicate that complex ISG15 interactions with DNA replication/repair factors can drive PARPi resistance in BRCA1-deficient cancer cells and that targeting ISG15 has the potential to overcome PARPi resistance.
2026-08-18 | GSE308092 | GEO
Project description:The use of poly(ADP-ribose) polymerase inhibitors (PARPi) has proven largely successful in targeting BRCA1/2-mutated tumours. However, the emergence of PARPi-resistant disease can reduce the efficacy of this treatment, posing significant challenges in the clinic. Here, we use multiple models of BRCA1-/- cells and patient-derived xenografts (PDXs) that have been treated with PARPi until they no longer responded to the drug, to characterise genomic and transcriptomic alterations specific to PARPi resistance. We find that abrogation of TP53BP1 expression occurs spontaneously during prolonged PARPi treatment, alongside TP53BP1 genomic deletions and promoter methylation. Additionally, innate immune response genes, including ISG15 and factors of the ISGylation machinery are upregulated in PARPi-resistant cells and tumours. We demonstrate that ISG15 inhibition re-sensitises PARPi-resistant cells to the drug and, conversely, that ISG15 overexpression in BRCA1-/- cells promotes PARPi resistance. Mechanistically, BRCA1-/- PARPi-resistant cells rely on ISG15 for replication fork progression and restart of stalled forks and for DNA double-strand break (DSB) repair via homologous recombination (HR). Our results indicate that complex ISG15 interactions with DNA replication/repair factors can drive PARPi resistance in BRCA1-deficient cancer cells and that targeting ISG15 has the potential to overcome PARPi resistance.
2026-08-18 | GSE308090 | GEO
Project description:Most BRCA1-deficient BLBCs carry a dysfunctional INK4-RB pathway. Thus, we have created genetically engineered mice with Brca1 loss and deletion of p16INK4A, or separately p18INK4C, to model the deficient INK4-RB signaling in human BLBC. By using these mutant mice and human BRCA1 deficient and proficient breast cancer tissues and cells, we tested if there exists a druggable target in BRCA1 deficient breast cancers.
2021-01-27 | GSE155239 | GEO
Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie Dropseq.
2021-11-17 | GSE148566 | GEO