目的研究BARD1(BRCA1 associated RING domain)在新疆维吾尔族妇女乳腺癌及癌旁组织中的表达情况及其临床意义。方法应用PV-9000免疫组化两步法检测103例维吾尔族妇女乳腺癌及癌旁石蜡包埋组织中BARD1的表达情况,分析BARD1的表达与患者...目的研究BARD1(BRCA1 associated RING domain)在新疆维吾尔族妇女乳腺癌及癌旁组织中的表达情况及其临床意义。方法应用PV-9000免疫组化两步法检测103例维吾尔族妇女乳腺癌及癌旁石蜡包埋组织中BARD1的表达情况,分析BARD1的表达与患者年龄、肿块大小、临床分期、淋巴结转移、绝经情况、组织分级、病理分型及雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体(HER-2)表达之间的关系,并分析其与乳腺癌预后之间的关系。结果(1)103例维吾尔族妇女乳腺癌及癌旁组织中BARD1的阳性表达率分别为59.22%(61/103)、72.82%(75/103),乳腺癌组织中BARD1的表达低于癌旁组织,两组之间的差异有统计学意义(P<0.05);BARD1在乳腺癌中的阳性表达部位在胞浆,在癌旁对照组织的阳性表达部位除了胞浆外,也见于胞核;BARD1在癌组织中的表达随肿块直径、临床分期、组织分级的不同其分布不同,差异有统计学意义(P<0.05)。(2)维吾尔族妇女乳腺癌组织中BARD1的表达与ER、PR、Her-2的表达之间不存在关联关系(P>0.05)。(3)BARD1表达越强,患者术后无瘤生存率越高(P<0.05)。结论BARD1基因蛋白的低表达或缺失在新疆维吾尔族妇女乳腺癌的发生、发展过程中起重要的作用,BARD1蛋白表达检测对新疆维吾尔族妇女乳腺癌的预后判断具有重要的指导意义。展开更多
目的通过检测乳腺黏液癌（以M表述）及浸润性导管癌（符合基底细胞样癌分子分型诊断标准：以D-B表述）标本中乳腺癌阻抑蛋白1关联RING蛋白1（BRCA1-associated RING domain,BARD1）剪切变异体表达水平的差异,结合术后随访结果,探讨BARD...目的通过检测乳腺黏液癌（以M表述）及浸润性导管癌（符合基底细胞样癌分子分型诊断标准：以D-B表述）标本中乳腺癌阻抑蛋白1关联RING蛋白1（BRCA1-associated RING domain,BARD1）剪切变异体表达水平的差异,结合术后随访结果,探讨BARD1基因在乳腺癌中可能的临床意义。方法以本院乳腺中心标本库储存的43例M标本及39例D-B标本提取的目的基因进行RT-PCR,对相应病例石蜡包埋组织切片进行病理免疫组织化学检测;患者术后每半年随访1次,记录无病生存期（disease free survival,DFS）及总生存期（overall survival,OS）;分析BARD1基因的临床意义。结果在所有标本中共发现4种BARD1基因的转录产物：全长BARD1基因（full lenth,Fl）,剪切变异体γ、δ和ε,其中Fl在所有组织中均有表达,剪切变异体δ和ε在M中的阳性表达率低于D-B（P〈0.005）;免疫组织化学检测发现在D-B中BARD1蛋白阳性细胞比率显著高于M（P〈0.005）,两种癌组织中蛋白均异位表达于细胞质中;BARD1剪切变异体的阳性表达与乳腺癌预后差的因素有关（P〈0.05）。研究病例术后随访36~70个月,单因素分析发现,剪切变异体ε阳性表达与乳腺癌术后无病生存期及总生存期缩短均显著相关（P〈0.05）。结论 BARD1剪切变异体在不同类型乳腺癌中的表达存在差异;与正常组织细胞相比,BARD1剪切变异体异位表达在肿瘤细胞质中;剪切变异体δ和ε与乳腺癌预后差的因素相关,并且剪切变异体ε阳性表达的患者无病生存期及总生存期均显著缩短。因此BARD1剪切变异体的异常表达或许影响乳腺癌的生物学行为,进而影响乳腺癌的预后。展开更多
目的:分析乳腺浸润性导管癌组织中BRCA1-asso-ciated RING domain 1(BARD1)与其相关蛋白c-erbB-2、P53、ER、PR表达的相关性及其与临床病理指标的关系,探讨BRAD1蛋白表达对乳腺癌诊断和治疗的意义。方法:通过免疫组织化学SP法,检测156...目的:分析乳腺浸润性导管癌组织中BRCA1-asso-ciated RING domain 1(BARD1)与其相关蛋白c-erbB-2、P53、ER、PR表达的相关性及其与临床病理指标的关系,探讨BRAD1蛋白表达对乳腺癌诊断和治疗的意义。方法:通过免疫组织化学SP法,检测156例乳腺浸润性导管癌和22例乳腺腺病中BARD1、c-erbB-2、P53、ER和PR的表达。结果:①浸润性导管癌中BARD1、c-erbB-2、P53、ER和PR蛋白的阳性表达率分别为59.0%(92/156)、76.9%(120/156)、36.5%(57/156)、45.5%(71/156)和51.3%(80/156);腺病组织中各蛋白的阳性表达率分别为91.0%(20/22)、13.6%(3/22)、9.1%(2/22)、72.7%(16/22)、72.7%(16/22),各蛋白在两组中的阳性表达差异均有统计学意义(P<0.05)。②乳腺浸润性导管癌组织中BARD1的表达与P53相关,而与c-erbB-2、ER和PR的表达无关联性。③BARD1在乳腺浸润性导管癌中的表达与肿瘤大小、临床分级和组织学分级相关。结论:乳腺浸润性导管癌中,BARD1低表达或缺失与肿瘤大小、组织学分级及临床分级相关,BARD1检测对乳腺癌的预后评估具有重要的指导意义。展开更多
Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair...Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation.The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination(HR)DSB repair,and its functions may be affected by HERC2 or BAP1.Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes;however,the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn’t been defined.Through activity-based profiling,we identified PT33 as an active entity for HR repair suppression.Subsequently,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen.Mechanistically,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR repair.Consequently,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo.Overall,these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.展开更多
文摘目的研究BARD1(BRCA1 associated RING domain)在新疆维吾尔族妇女乳腺癌及癌旁组织中的表达情况及其临床意义。方法应用PV-9000免疫组化两步法检测103例维吾尔族妇女乳腺癌及癌旁石蜡包埋组织中BARD1的表达情况,分析BARD1的表达与患者年龄、肿块大小、临床分期、淋巴结转移、绝经情况、组织分级、病理分型及雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体(HER-2)表达之间的关系,并分析其与乳腺癌预后之间的关系。结果(1)103例维吾尔族妇女乳腺癌及癌旁组织中BARD1的阳性表达率分别为59.22%(61/103)、72.82%(75/103),乳腺癌组织中BARD1的表达低于癌旁组织,两组之间的差异有统计学意义(P<0.05);BARD1在乳腺癌中的阳性表达部位在胞浆,在癌旁对照组织的阳性表达部位除了胞浆外,也见于胞核;BARD1在癌组织中的表达随肿块直径、临床分期、组织分级的不同其分布不同,差异有统计学意义(P<0.05)。(2)维吾尔族妇女乳腺癌组织中BARD1的表达与ER、PR、Her-2的表达之间不存在关联关系(P>0.05)。(3)BARD1表达越强,患者术后无瘤生存率越高(P<0.05)。结论BARD1基因蛋白的低表达或缺失在新疆维吾尔族妇女乳腺癌的发生、发展过程中起重要的作用,BARD1蛋白表达检测对新疆维吾尔族妇女乳腺癌的预后判断具有重要的指导意义。
文摘目的:分析乳腺浸润性导管癌组织中BRCA1-asso-ciated RING domain 1(BARD1)与其相关蛋白c-erbB-2、P53、ER、PR表达的相关性及其与临床病理指标的关系,探讨BRAD1蛋白表达对乳腺癌诊断和治疗的意义。方法:通过免疫组织化学SP法,检测156例乳腺浸润性导管癌和22例乳腺腺病中BARD1、c-erbB-2、P53、ER和PR的表达。结果:①浸润性导管癌中BARD1、c-erbB-2、P53、ER和PR蛋白的阳性表达率分别为59.0%(92/156)、76.9%(120/156)、36.5%(57/156)、45.5%(71/156)和51.3%(80/156);腺病组织中各蛋白的阳性表达率分别为91.0%(20/22)、13.6%(3/22)、9.1%(2/22)、72.7%(16/22)、72.7%(16/22),各蛋白在两组中的阳性表达差异均有统计学意义(P<0.05)。②乳腺浸润性导管癌组织中BARD1的表达与P53相关,而与c-erbB-2、ER和PR的表达无关联性。③BARD1在乳腺浸润性导管癌中的表达与肿瘤大小、临床分级和组织学分级相关。结论:乳腺浸润性导管癌中,BARD1低表达或缺失与肿瘤大小、组织学分级及临床分级相关,BARD1检测对乳腺癌的预后评估具有重要的指导意义。
基金supported by the National Natural Science Foundation of China(NSFC)(No.82272743 to Xin Yue(82172812)of NSFC to Ran-yi Liu+4 种基金81871996 to Ran-yi Liu82003218 to Xuecen Wang82072029 to Zhenwei Peng and 81973174 to Xianzhang Bu)Guangdong Basic and Applied Basic Research Foundation(No.2021A1515012496 to Xin Yue and 2022A1515012221 to Xianzhang Bu)Basic Scientific Research Operation of Sun Yat-sen University(No.19ykpy192 to Xin Yue)。
文摘Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation.The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination(HR)DSB repair,and its functions may be affected by HERC2 or BAP1.Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes;however,the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn’t been defined.Through activity-based profiling,we identified PT33 as an active entity for HR repair suppression.Subsequently,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen.Mechanistically,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR repair.Consequently,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo.Overall,these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.
