RAD6B is a major mediator of triple negative breast cancer cisplatin resistance: Regulation of translesion synthesis/Fanconi anemia crosstalk and BRCA1 independence

Publication date: Available online 19 October 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Brittany Haynes, Ambikai Gajan, Pratima Nangia-Makker, Malathy P. ShekharAbstractTriple negative breast cancer (TNBC) is an aggressive breast cancer subtype with few therapy options besides chemotherapy. Although platinum-based drugs have shown initial activity in BRCA1-mutated TNBCs, chemoresistance remains a challenge. Here we show that RAD6B (UBE2B), a principal mediator of translesion synthesis (TLS), is overexpressed in BRCA1 wild-type and mutant TNBCs, and RAD6B overexpression correlates with poor survival. Pretreatment with a RAD6-selective inhibitor, SMI#9, enhanced cisplatin chemosensitivity of BRCA1 wild-type and mutant TNBCs. SMI#9 attenuated cisplatin-induced PCNA monoubiquitination (TLS marker), FANCD2 (Fanconi anemia (FA) activation marker), and TLS polymerase POL η. SMI#9-induced decreases in γH2AX levels were associated with concomitant inhibition of H2AX monoubiquitination, suggesting a key role for RAD6 in modulating cisplatin-induced γH2AX via H2AX monoubiquitination. Concordantly, SMI#9 inhibited γH2AX, POL η and FANCD2 foci formation. RAD51 foci formation was unaffected by SMI#9, however, its recruitment to double-strand breaks was inhibited. Using the DR-GFP-based assay, we showed that RAD6B silencing or SMI#9 treatment impairs homologous recombination (HR) in HR-proficient cells. DNA fiber assays ...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research

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VOLUME 287 (2012) PAGES 3366–3380The comet sub-panels in Fig. S4 were erroneously copied during figure assembly. This error has now been corrected using the original files. These changes do not affect the results or conclusions of this work. The authors sincerely apologize for the error.jbc;294/35/13198/FU1F1FU1
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Additions and Corrections Source Type: research
ConclusionOur data expand the clinical spectrum associated with biallelicBRCA1 mutations, ranging from embryonic lethality to a mild FA ‐like phenotype and no chromosome fragility.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: ORIGINAL ARTICLE Source Type: research
BReast Cancer Associated proteins 1 and 2 (BRCA1, -2) and Partner and Localizer of BRCA2 (PALB2) protein are tumor suppressors linked to a spectrum of malignancies, including breast cancer and Fanconi anemia. PALB2 coordinates functions of BRCA1 and BRCA2 during homology-directed repair (HDR) and interacts with several chromatin proteins. In addition to protein scaffold function, PALB2 binds DNA. The functional role of this interaction is poorly understood. We identified a major DNA-binding site of PALB2, mutations in which reduce RAD51 foci formation and the overall HDR efficiency in cells by 50%. PALB2 N-terminal DNA-bin...
Source: eLife - Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cancer Biology Source Type: research
Yi-Cheng Gao, Xiong-Hui Zhou* and Wen Zhang* Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China Due to the high heterogeneity and complexity of cancer, it is still a challenge to predict the prognosis of cancer patients. In this work, we used a clustering algorithm to divide patients into different subtypes in order to reduce the heterogeneity of the cancer patients in each subtype. Based on the hypothesis that the gene co-expression network may reveal relationships among genes, some communities in the network could influence the prognosis o...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
This study analyzed the genetic susceptibility of gene polymorphisms in three patients with multiple primary malignant neoplasms and examined the possible pathogenesis. The clinical data and whole genome sequence of three patients (1 with 5 primary cancers, 1 with 4 primary cancers, and 1 with 3 primary cancers) were aligned with a series of databases. We found the three patients contained a total of seven types of malignant tumours (endometrial cancer, ovarian cancer, breast cancer, colon cancer, ureter cancer, bladder cancer and kidney cancer). It was found that the varied genes in Patient 1 (5 primary cancers) were BRIP...
Source: Artificial Cells, Nanomedicine and Biotechnology - Category: Biotechnology Tags: Artif Cells Nanomed Biotechnol Source Type: research
In conclusion, the present study suggested that BRCA1 and FANCD2 expression, and FANCD2 ubiquitination levels, may be considered of novel potential prognostic value in patients with BC. PMID: 30881493 [PubMed]
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
ada Cancer is a disease driven by both somatic mutations that increase survival and proliferation of cell lineages and the evolution of genes associated with cancer risk in populations. Several genes associated with cancer in humans, hereafter cancer genes, show evidence of germline positive selection among species. Taking advantage of a large collection of mammalian genomes, we systematically looked for signatures of germline positive selection in 430 cancer genes available in COSMIC. We identified 40 cancer genes with a robust signal of positive selection in mammals. We found evidence for fewer selective constraints&...
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Article Source Type: research
ConclusionsAmong AJ patients found to have a pathogenic mutation on genetic assessment, approximately 22.8% had a mutation that would be missed with BRCA1/2 AJ founder mutation testing. Comprehensive multigene panel sequencing can provide clinically relevant genetic information for AJ patients and should be considered for genetic assessment in this population.
Source: Cancer - Category: Cancer & Oncology Authors: Tags: Original Article Source Type: research
In this study, we performed comprehensive germline and somatic mutation profiling in t-MN using next generation sequencing. Matched germline material was available for 62/194 (32%) patients. Mutation profiling was correlated with clinical features including family history in 194 patients enrolled in the South Australian MDS (SA-MDS) registry and Cleveland Clinic (CC). An in-house well established filtering pipeline was used for identification of somatic mutations. Only variants with Genome Aggregation Database (gnomAD) minor allele frequency (MAF) of ≤0.01% and variant allele frequency (VAF) of ≥35% were selected for...
Source: Blood - Category: Hematology Authors: Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Poster I Source Type: research
Discussion: Our study includes 94 families. Twenty-one cancers were reported in 188 parents, with 24 expected (O/E 0.86, 95% CI [confidence interval] 0.53-1.31). Three hundred and twenty-seven grandparents had 89 cases with cancer, expected 125 (O/E 0.71, CI 0.57-0.88). There were 122 siblings, with 1 cancer case and 4 expected (O/E 0.26, CI 0.01-1.46). Among 12 offspring there was 1 case of leukemia (O/E 1:0.12, CI 0.2-44.64). Specific cancers had increased O/E in parents (2 cases of salivary gland cancer, O/E 27.3, CI 3.31-98.66), grandparents (5 with liver cancer O/E 4.7, CI 1.53-10.96; 9 with leukemia O/E 2.42, CI 1.11...
Source: Blood - Category: Hematology Authors: Tags: 508. Bone Marrow Failure: Poster III Source Type: research
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