Comparison of aCGH profiles from KB1(185stop)P, KB1(5382stop)P and KB1P mouse mammary tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE43997 | GEO | 2013/12/01
SECONDARY ACCESSION(S): PRJNA188321
REPOSITORIES: GEO
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Project description:While BRCA-related cancers respond well to double-strand break (DSB) inducing agents, resistance is a serious clinical problem. One mechanism of resistance is reversion of the BRCA1 mutation, suggesting that BRCA1 function is required for resistance. Here we show that secondary Brca1 mutations are not always necessary, since residual activity of the mutant BRCA1 protein can be sufficient for tumor cells to withstand treatment. Genomic profiling and RAD51 foci formation are currently seen as potential biomarkers to stratify patients for therapies targeting homologous recombination deficiency (HRD). However, we show that while mouse mammary tumors with different Brca1 mutations have identical genomic profiles, they respond considerably different to HRD targeted therapy. It may therefore be useful to stratify patients according to functional assays and the underlying BRCA1 mutation. We performed aCGH on mammary tumor DNA from KB1C61GP (n=20), littermate KB1P (n=18) and KP mice (n=19). Spleen DNA of the same animal was used as control material.
2011-12-01 | E-GEOD-30710 | biostudies-arrayexpress
Project description:While BRCA-related cancers respond well to double-strand break (DSB) inducing agents, resistance is a serious clinical problem. One mechanism of resistance is reversion of the BRCA1 mutation, suggesting that BRCA1 function is required for resistance. Here we show that secondary Brca1 mutations are not always necessary, since residual activity of the mutant BRCA1 protein can be sufficient for tumor cells to withstand treatment. Genomic profiling and RAD51 foci formation are currently seen as potential biomarkers to stratify patients for therapies targeting homologous recombination deficiency (HRD). However, we show that while mouse mammary tumors with different Brca1 mutations have identical genomic profiles, they respond considerably different to HRD targeted therapy. It may therefore be useful to stratify patients according to functional assays and the underlying BRCA1 mutation. We performed aCGH on mammary tumor DNA from KB1(185stop)P (n=20), KB1(5382stop)P (n=20) and littermate KB1P (n=22). Spleen DNA of the same animal was used as control material.
2013-12-01 | E-GEOD-43997 | biostudies-arrayexpress
Project description:While BRCA-related cancers respond well to double-strand break (DSB) inducing agents, resistance is a serious clinical problem. One mechanism of resistance is reversion of the BRCA1 mutation, suggesting that BRCA1 function is required for resistance. Here we show that secondary Brca1 mutations are not always necessary, since residual activity of the mutant BRCA1 protein can be sufficient for tumor cells to withstand treatment. Genomic profiling and RAD51 foci formation are currently seen as potential biomarkers to stratify patients for therapies targeting homologous recombination deficiency (HRD). However, we show that while mouse mammary tumors with different Brca1 mutations have identical genomic profiles, they respond considerably different to HRD targeted therapy. It may therefore be useful to stratify patients according to functional assays and the underlying BRCA1 mutation.
2011-12-01 | GSE30710 | GEO
Project description:BRCA1 loss leads to tumor cell transcriptional reprogramming, resulting in a DNA damage-driven, mandatory cell-autonomous type I IFN inflammatory activation mediated by STING and TREX1/2. PARP inhibition augmented this immunoreactivity, creating contextual lethality to dual immune checkpoint blockade (ICB) in vivo. BRCA1-deficient tumor can escape T-cell inflammation through targeted deletion or methylation of the DNA sensing/IFN pathway genes, such as STING, IFNB1 or the chemokine CCL5. Alternatively, BRCA-mutated carcinomas retaining immunoreactivity upregulate their VEGF-A expression driven by STING, which mediates immune resistance and tumor progression. STING elimination attenuated tumor growth and abrogated therapeutic resistance to dual ICB. VEGF-A blockade synergized with immune checkpoint blockade and/or PARP inhibition to control outgrowth of Brca1-/- ovarian tumors, offering opportunities for rational combination therapy of cancers with homologous recombination repair deficiency (HRD).
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