Somatic Inactivation of Breast Cancer Predisposition Genes in Tumours Associated with Pathogenic Germline Variants
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PROVIDER: EGAS00001006532 | EGA |
REPOSITORIES: EGA
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Project description:By blocking poly ADP ribose polymerase (PARP), olaparib prevents DNA damage repair, particularly in tumors that have a BRCA1/2 mutation or are BRCA-positive. Nevertheless, a Phase II study of 33 CRC patients receiving mono-Olaparib therapy revealed that some of these individuals still had resistance to Olaparib while having poor DNA damage repair. RAD51 reversion mutations are a frequent cause of resistance to PARP inhibitors in cancers that do not have BRCA mutations. Though little is known, a number of tactics have been studied when combining PARPi with other inhibitors. Here, we introduce the enzyme KAT2B as a protein involved in transcription that is connected to RAD51C, reducing the levels of RAD51C by lowering the acetylation of Histone H3 (H3K27) at the beginning of the RAD51C gene. Consequently, colorectal cancer cells become more vulnerable to Olaparib therapy. The H3K27ac binding domain is necessary for the transcription of RAD51C. We find that a subpopulation of tumor cells expressing RAD51C have reduced endogenous KAT2B expression. This expression leads to increased DNA damage accumulation and decreased PARPi resistance in RAD51C-expressing cells. According to our findings, RAD51C-expressing cells' RAD51C and PARPi responses are significantly regulated by KAT2B and histone acetylation. This information offers vital new understandings into the molecular requirements for focusing on BRCA-functional malignancies.
2026-03-18 | GSE267911 | GEO
Project description:Double-strand break (DSB) damage are primarily repaired via homologous recombination (HR) and non-homologous end joining (NHEJ) in Eukaryotes. We reveals that HR subcomplex RAD51A1-RAD51C in rice (Oryza sativa L.) inhibits classic NHEJ pathway while acts as a transcriptional mediator underlying alternative NHEJ signaling. RAD51C hijacks the KU70 at DSBs, facilitated by its partner RAD51A1 or TOP6B responding environmental cues (pathogens and 4℃). Consequently, the enhanced alternative NHEJ signaling generates the phosphorylated SOG1, which activates the regulatory network in diterpenoid phytoalexin biosynthesis and a group of enzyme genes in phenylpropanoid pathway. Intriguingly, SOG1-BRCA1-RAD51 associates with RAD51C-RAD51D-XRCC3 to form a transcription pre-initiation complex in this process. Phenotypically, chemical disease resistance and 4℃-conditioned stomatal closure are compromised in single mutants (atm-3, sog1, and rad51c-1), double mutants (rad51a1 rad51a2 and rad51d xrcc3). In summary, HR pathway integrates classic and alternative NHEJ pathways to orchestrate stress-activated specific metabolism in rice. Hierarchical collaboration of global DSB-repair machinerys enable plant adaptability to DSB-related environmental stresses.
2025-01-30 | GSE288025 | GEO
Project description:Double-strand break (DSB) damage are primarily repaired via homologous recombination (HR) and non-homologous end joining (NHEJ) in Eukaryotes. We reveals that HR subcomplex RAD51A1-RAD51C in rice (Oryza sativa L.) inhibits classic NHEJ pathway while acts as a transcriptional mediator underlying alternative NHEJ signaling. RAD51C hijacks the KU70 at DSBs, facilitated by the interacting partner RAD51A1 or TOP6B responding environmental cues (pathogens and 4℃). Consequently, the enhanced alternative NHEJ signaling generates the phosphorylated SOG1, which activates the regulatory network in diterpenoid phytoalexin biosynthesis and a group of genes in phenylpropanoid pathway. Intriguingly, SOG1-BRCA1-RAD51 associates with RAD51C-RAD51D-XRCC3 forming a transcription pre-initiation complex in this process. Phenotypically, chemical disease resistance and 4℃-conditioned stomatal closure are compromised in single mutants (atm-3, sog1, and rad51c-1), double mutants (rad51a1 rad51a2 and rad51d xrcc3). In summary, HR pathway integrates classic and alternative NHEJ pathways to orchestrate stress-activated specific metabolism in rice plants. Hierarchical functional collaboration of global DSB-repair machinerys enable plant adaptability to DSB-related environmental stresses.
2025-01-27 | GSE287659 | GEO
Project description:Palb2 interacts with BRCA1 and BRCA2 in supercomplexes involved in DNA repair via homologous recombination. Heterozygous germline mutations in PALB2 confer a moderate risk of breast cancer while biallelic PALB2 mutations are linked to a severe form of Fanconi anaemia characterized by early childhood solid tumours and severe chromosomal instability. In contrast to BRCA1- or BRCA2-associated cancers, breast tumours in heterozygous PALB2 mutation carriers do not show loss of the wild type allele, suggesting PALB2 might be haploinsufficient for tumour suppression. To study the role of PALB2 in development and tumourigenesis, we have generated Palb2GT mouse mutants using a gene trap approach. Whereas Palb2GT/GT homozygous mutant embryos died at mid-gestation due to massive apoptosis, Palb2GT/+ heterozygous mice were viable and did not show any obvious abnormalities. Deletion of p53 alleviated the phenotype of Palb2GT/GT embryos, but did not rescue embryonic lethality. In addition, loss of p53 did not significantly collaborate with Palb2 heterozygosity in tumourigenesis in heterozygous or homozygous p53 knockout mice. Tumours arising in Palb2GT/+;p53+/– or Palb2GT/+;p53–/– compound mutant mice retained the wild type Palb2 allele and did not display increased genomic instability.
2011-01-21 | GSE26723 | GEO
Project description:PArtner and Localizer of BRCA2 (PALB2) is essential to maintain genome stability in human cells. Upon DNA damage by double DNA strand breaks, PALB2 is required to repair DNA by homologous recombination. In undamaged conditions, PALB2 protects coding regions, by preventing DNA stress due to collisions between transcription and replication machineries. PALB2 associates with chromatin, which is essential to fulfill its function in genome stability maintenance, however molecular mechanisms regulating PALB2 chromatin association remain unknown. In our previous published study describing the KAT2A/B(GCN5/PCAF)-acetylome (Fournier et al., Nat.Comm. 2016, doi: 10.1038/ncomms13227) we have identified PALB2 as an acetylated protein target of the acetyltransferases KAT2A (GCN5) and KAT2B (PCAF) in vivo. KAT2A/B-acetylated sites of PALB2 were mapped within its DNA/Chromatin association domain. In this current study, we have conducted in vitro acetyltransferase (AT) assays, by mixing purified recombinant GST-tagged PALB2 full-length (FL) and PALB2 fragment P2.2 which associates with DNA/chromatin (from residues 295-610), with Flag-PCAF, Flag-GCN5 and Flag-GCN5 catalytic mutant (mut), followed by proteomics analysis to map PALB2 acetylated lysines by KAT2A(GCN5) and KAT2B(PCAF) in vitro. PALB2 FL and P2.2 alone, or PALB2 FL and P2.2 mixed with GCN5 catalytic mutant, were used as negative controls.
2023-03-10 | PXD014681 | Pride
Project description:Palb2 interacts with BRCA1 and BRCA2 in supercomplexes involved in DNA repair via homologous recombination. Heterozygous germline mutations in PALB2 confer a moderate risk of breast cancer while biallelic PALB2 mutations are linked to a severe form of Fanconi anaemia characterized by early childhood solid tumours and severe chromosomal instability. In contrast to BRCA1- or BRCA2-associated cancers, breast tumours in heterozygous PALB2 mutation carriers do not show loss of the wild type allele, suggesting PALB2 might be haploinsufficient for tumour suppression. To study the role of PALB2 in development and tumourigenesis, we have generated Palb2GT mouse mutants using a gene trap approach. Whereas Palb2GT/GT homozygous mutant embryos died at mid-gestation due to massive apoptosis, Palb2GT/+ heterozygous mice were viable and did not show any obvious abnormalities. Deletion of p53 alleviated the phenotype of Palb2GT/GT embryos, but did not rescue embryonic lethality. In addition, loss of p53 did not significantly collaborate with Palb2 heterozygosity in tumourigenesis in heterozygous or homozygous p53 knockout mice. Tumours arising in Palb2GT/+;p53+/– or Palb2GT/+;p53–/– compound mutant mice retained the wild type Palb2 allele and did not display increased genomic instability. Comparison of 15 Palb2GT/+;p53-/- and 11 Palb2+/+;p53-/- lymphomas. Spleen/liver DNA of the same animal was used as reference material.
2011-01-21 | E-GEOD-26723 | biostudies-arrayexpress
Project description:NGS-based multiple gene panel resequencing in combination with a high resolution CGH-array was used to identify genetic risk factors for hereditary breast and/or ovarian cancer in 237 high risk patients who were previously tested negative for pathogenic BRCA1/2 variants. All patients were screened for pathogenic variants in 94 different cancer predisposing genes. We identified 32 pathogenic variants in 14 different genes (ATM, BLM, BRCA1, CDH1, CHEK2, FANCG, FANCM, FH, HRAS, PALB2, PMS2, PTEN, RAD51C and NBN) in 30 patients (12.7%). Two pathogenic BRCA1 variants that were previously undetected due to less comprehensive and sensitive methods were found. Five pathogenic variants are novel, three of which occur in genes yet unrelated to hereditary breast and/or ovarian cancer (FANCG, FH and HRAS). In our cohort we discovered a remarkably high frequency of truncating variants in FANCM (2.1%), which has recently been suggested as a susceptibility gene for hereditary breast cancer. Two patients of our cohort carried two different pathogenic variants each and ten other patients in whom a pathogenic variant was confirmed also harbored a variant of unknown significance in a breast and ovarian cancer susceptibility gene. We were able to identify pathogenic variants predisposing for tumor formation in 12.3% of BRCA1/2 negative breast and/or ovarian cancer patients.
2018-10-31 | GSE121968 | GEO
Project description: Not available
| S-EPMC12428717 | biostudies-literature
Project description:Breast Cancer (BC) is one of the most common cancers and one of the most common causes for cancer- related mortality. Discovery of protein biomarkers associated with cancer, is considered as important for early diagnosis and prediction of the cancer risk. Protein biomarkers could be investigated by large-scale protein investigation or proteomics, using mass spectrometry (MS)- based techniques. Our group applies MS-based proteomics to study the protein pattern in human breast milk from women with BC and controls and investigates the alterations and dysregula-tions of breast milk proteins in comparison pairs of BC versus control. These dysregulated pro-teins might be considered as potential future biomarkers of BC. Identification of potential bi-omarkers in breast milk may benefit young women without BC, but who could collect the milk for future assessment of BC risk. Previously we identified several dysregulated proteins in dif-ferent sets of human breast milk samples from BC patients and controls using gel-based protein separation coupled with MS. Here, we performed two-dimensional polyacrylamide gel electro-phoresis (2D-PAGE) coupled with nano-liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) in a small-scale study on a set of 6 human breast milk samples (3 BC samples vs. 3 controls) and we identified several dysregulated proteins which have potential roles in cancer progression and might be considered as potential BC biomarkers in the future.
2023-10-20 | PXD040188 | Pride
Project description:Breast and ovarian cancer susceptibility genes, BRCA1 and PALB2 have enigmatic roles in cellular growth and mammalian development. While these genes are essential for growth during early developmental programs, inactivation later in adulthood leads to increased growth and formation of tumors, leading to their designation as tumor suppressors. We performed genome-wide analysis assessing their chromatin residence and gene expression responsiveness using high throughput sequencing in breast epithelial cells. These experiments revealed a critical role for BRCA1 and PALB2 in transcriptional responsiveness to NF-kB, a crucial mediator of growth and inflammatory response during development and cancer. Importantly, we also uncovered a vital role for these proteins in response to retinoic acid (RA), a growth inhibitory signal in breast cancer cells, which may constitute the basis for their tumor suppressor activity. Comparison of the genome wide profiles of the BRCA protein complex (BRCA1 and PALB2) and phosphorylated RNAPII (P-Ser2) in MCF10A cells by ChIP-seq. Effect of BRCA1 and PALB2 knockdown (shRNAs) on transcription was assessed by RNA-seq.
2013-09-30 | E-GEOD-40591 | biostudies-arrayexpress