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• W2563767713 abstract "Purpose/Objective(s)Sporadic breast cancer accounts for 80-85% of all breast cancer. A subset of sporadic breast cancers is associated with functional inactivation of BRCA1 and displays a basal-like phenotype similar to hereditary BRCA1-associated breast cancers. The BRCA1 inactivation phenotype is sometimes referred to as “BRCAness.” Association of BRCAness with specific chemosensitivity has been suggested, but is not well defined in clinical response data. Our goal is to identify and characterize the BRCAness phenotype among sporadic breast cancer cell lines by examining homologous recombination (HR) proficiency. We hypothesize that tumors showing deficiency in HR can have normal BRCA1 protein expression, but fail to recruit BRCA1 to sites of DNA damage.Materials/MethodsHR deficiency was initially detected by formation of RAD51 foci and further characterized by colony survival and HR functional assay using flow cytometry. For RAD51 focus formation, DNA double-strand breaks (DSB) were induced by irradiation, cells were stained for RAD51, and foci were counted using confocal microscopy. For colony survival assay, interstrand crosslinks (ICLs) were induced with mitomycin-C; colony formation was assessed after 2 week incubation. To measure HR, the DR-GFP plasmid was transfected into cells, DNA DSB was induced, and flow cytometry was used to assess the extent of induced GFP expression. DR-GFP was assayed +/-BRCA1 siRNA knockdown to evaluate whether HR was influenced by additional BRCA1 protein depletion.ResultsThe MCF7 and MDA-MB-231 cell lines each demonstrated >2-fold induction of RAD51 foci in irradiated cells over baseline. HCC202 showed no significant RAD51 foci induction, while HCC1428 were only weakly inducing suggesting a functional RAD51 defect. Colony survival showed relative insensitivity of MDA-MB-231 to interstrand cross linking; MCF7 was intermediately sensitive to ICL formation while HCC1428 and HCC202 were highly sensitive. Preliminary flow cytometry suggested increased GFP expression among MCF7 and MDA-MB-231 cells after DSB induction, while HCC1428 showed no increase in GFP expression.ConclusionMCF7 and MDA-MB-231 cell lines are HR-proficient as shown by RAD51 recruitment to nuclear foci, response to ICL formation, and the DR-GRP assay. The cell lines HCC1428 and HCC202 are HR-defective as indicated by failure to recruit RAD51 foci to sites of DNA DSB, marked sensitivity to ICL formation, and reduced HR by DR-GFP. This characterization of HR-deficiency in breast cancer cell lines with normal BRCA1 protein expression will allow for further exploration into the mechanism of BRCAness. In addition, these experiments support the use of HR-deficiency targeting agents for sporadic cancers exhibiting BRCAness, which may be as prevalent as ∼25% of breast cancer. Purpose/Objective(s)Sporadic breast cancer accounts for 80-85% of all breast cancer. A subset of sporadic breast cancers is associated with functional inactivation of BRCA1 and displays a basal-like phenotype similar to hereditary BRCA1-associated breast cancers. The BRCA1 inactivation phenotype is sometimes referred to as “BRCAness.” Association of BRCAness with specific chemosensitivity has been suggested, but is not well defined in clinical response data. Our goal is to identify and characterize the BRCAness phenotype among sporadic breast cancer cell lines by examining homologous recombination (HR) proficiency. We hypothesize that tumors showing deficiency in HR can have normal BRCA1 protein expression, but fail to recruit BRCA1 to sites of DNA damage. Sporadic breast cancer accounts for 80-85% of all breast cancer. A subset of sporadic breast cancers is associated with functional inactivation of BRCA1 and displays a basal-like phenotype similar to hereditary BRCA1-associated breast cancers. The BRCA1 inactivation phenotype is sometimes referred to as “BRCAness.” Association of BRCAness with specific chemosensitivity has been suggested, but is not well defined in clinical response data. Our goal is to identify and characterize the BRCAness phenotype among sporadic breast cancer cell lines by examining homologous recombination (HR) proficiency. We hypothesize that tumors showing deficiency in HR can have normal BRCA1 protein expression, but fail to recruit BRCA1 to sites of DNA damage. Materials/MethodsHR deficiency was initially detected by formation of RAD51 foci and further characterized by colony survival and HR functional assay using flow cytometry. For RAD51 focus formation, DNA double-strand breaks (DSB) were induced by irradiation, cells were stained for RAD51, and foci were counted using confocal microscopy. For colony survival assay, interstrand crosslinks (ICLs) were induced with mitomycin-C; colony formation was assessed after 2 week incubation. To measure HR, the DR-GFP plasmid was transfected into cells, DNA DSB was induced, and flow cytometry was used to assess the extent of induced GFP expression. DR-GFP was assayed +/-BRCA1 siRNA knockdown to evaluate whether HR was influenced by additional BRCA1 protein depletion. HR deficiency was initially detected by formation of RAD51 foci and further characterized by colony survival and HR functional assay using flow cytometry. For RAD51 focus formation, DNA double-strand breaks (DSB) were induced by irradiation, cells were stained for RAD51, and foci were counted using confocal microscopy. For colony survival assay, interstrand crosslinks (ICLs) were induced with mitomycin-C; colony formation was assessed after 2 week incubation. To measure HR, the DR-GFP plasmid was transfected into cells, DNA DSB was induced, and flow cytometry was used to assess the extent of induced GFP expression. DR-GFP was assayed +/-BRCA1 siRNA knockdown to evaluate whether HR was influenced by additional BRCA1 protein depletion. ResultsThe MCF7 and MDA-MB-231 cell lines each demonstrated >2-fold induction of RAD51 foci in irradiated cells over baseline. HCC202 showed no significant RAD51 foci induction, while HCC1428 were only weakly inducing suggesting a functional RAD51 defect. Colony survival showed relative insensitivity of MDA-MB-231 to interstrand cross linking; MCF7 was intermediately sensitive to ICL formation while HCC1428 and HCC202 were highly sensitive. Preliminary flow cytometry suggested increased GFP expression among MCF7 and MDA-MB-231 cells after DSB induction, while HCC1428 showed no increase in GFP expression. The MCF7 and MDA-MB-231 cell lines each demonstrated >2-fold induction of RAD51 foci in irradiated cells over baseline. HCC202 showed no significant RAD51 foci induction, while HCC1428 were only weakly inducing suggesting a functional RAD51 defect. Colony survival showed relative insensitivity of MDA-MB-231 to interstrand cross linking; MCF7 was intermediately sensitive to ICL formation while HCC1428 and HCC202 were highly sensitive. Preliminary flow cytometry suggested increased GFP expression among MCF7 and MDA-MB-231 cells after DSB induction, while HCC1428 showed no increase in GFP expression. ConclusionMCF7 and MDA-MB-231 cell lines are HR-proficient as shown by RAD51 recruitment to nuclear foci, response to ICL formation, and the DR-GRP assay. The cell lines HCC1428 and HCC202 are HR-defective as indicated by failure to recruit RAD51 foci to sites of DNA DSB, marked sensitivity to ICL formation, and reduced HR by DR-GFP. This characterization of HR-deficiency in breast cancer cell lines with normal BRCA1 protein expression will allow for further exploration into the mechanism of BRCAness. In addition, these experiments support the use of HR-deficiency targeting agents for sporadic cancers exhibiting BRCAness, which may be as prevalent as ∼25% of breast cancer. MCF7 and MDA-MB-231 cell lines are HR-proficient as shown by RAD51 recruitment to nuclear foci, response to ICL formation, and the DR-GRP assay. The cell lines HCC1428 and HCC202 are HR-defective as indicated by failure to recruit RAD51 foci to sites of DNA DSB, marked sensitivity to ICL formation, and reduced HR by DR-GFP. This characterization of HR-deficiency in breast cancer cell lines with normal BRCA1 protein expression will allow for further exploration into the mechanism of BRCAness. In addition, these experiments support the use of HR-deficiency targeting agents for sporadic cancers exhibiting BRCAness, which may be as prevalent as ∼25% of breast cancer." @default.
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• W2563767713 date "2015-11-01" @default.
• W2563767713 modified "2023-10-16" @default.
• W2563767713 title "Sporadic Breast Cancer Cell Lines Show Homologous Recombination Deficiency From BRCA1 Pathway Inactivation With Normal BRCA1 Protein and Are Sensitive to Crosslinking Agents" @default.
• W2563767713 doi "https://doi.org/10.1016/j.ijrobp.2015.07.1868" @default.
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