PARP1和APE1在三阴乳腺癌中表达的相关性及临床意义
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摘要
目的探讨DNA损伤修复基因APE1及PARP1在人三阴乳腺癌的表达及其与临床病理特征、预后的相关性。方法选取2008年1月至2012年12月该院收治的60例三阴乳腺浸润性癌患者,采用免疫组化方法检测BRCA1、PARP1与APE1在三阴乳腺癌组织中的表达水平,分析其相关性表达及与肿瘤预后的相关性。结果三阴乳腺浸润性导管癌中APE1、PARP1和BRACI的阳性表达率分别为58.3%(35/60)、56.7%(34/60)和35.0%(21/60)。PARP1表达在腋窝淋巴结转移阳性的癌组织中表达水平明显高于腋窝淋巴结转移阴性,差异有统计学意义(P=0.009);而PARP1表达水平在发病年龄、肿瘤大小、组织分化及临床分期的分组间比较,差异均无统计学意义(P>0.05));APE1与PARP1表达水平呈正相关(r=0.489,P<0.001)。多因素Cox回归分析发现,年龄、腋窝淋巴结转移、组织分化差及APE1阳性表达是三阴乳腺癌独立的预后因子,能显著减少患者的生存时间。结论 APE1和PARP1在三阴乳腺浸润性导管癌中表达与不良预后有关,阻断APE1及PARP1信号通路,有望成为三阴浸润性乳腺癌的治疗新策略。
Objective To investigate the expression of DNA damage repair genes APE1 and PARP1 in human threenegative breast cancer and their correlations with clinicopathological features and prognosis. Methods Sixty patients withthree negative infiltrative breast cancer in this hospital from January 2008 to December 2012 were selected. The immunohisto-chemical method was adopted to examine the expression of BRCA1,PARP1 and APE1 in three negative breast cancer tissues.Then their correlation with the tumor prognosis was analyzed. Results The positive expressive rates of APE1,PARP1 andBRCA1 in three negative infiltrative ductal breast cancer were 58.3%(35/60),56.7%(34/60)and 35.0%(21/60)respectively.The PARP1 expression in cancer tissue of axillary lymph node metastasis positive was significantly higher than that in cancertissue of axillary lymph node metastasis negative,and the difference was statistically significant(P=0.009);whereas thePARP1 expression had no statistical difference among the onset age,tumor size,tissue differentiation and clinical stages(P>0.05);APE1 was positively correlated with PARP1 expression(r=0.489,P<0.001). The multiple factor Cox regression analysisindicated that the age,axillary lymph node metastasis,poor histological differentiation and APE1 positive expression were theindependent prognostic factors of three negative breast cancer. Conclusion The expression of APE and PARP1 is associatedwith poor prognosis in three-negative breast cancer,and blocking APE1 and PARP1 signaling pathways is expected to become anew therapeutic strategy for three negative infiltrative breast cancer.
Objective To investigate the expression of DNA damage repair genes APE1 and PARP1 in human threenegative breast cancer and their correlations with clinicopathological features and prognosis. Methods Sixty patients withthree negative infiltrative breast cancer in this hospital from January 2008 to December 2012 were selected. The immunohisto-chemical method was adopted to examine the expression of BRCA1,PARP1 and APE1 in three negative breast cancer tissues.Then their correlation with the tumor prognosis was analyzed. Results The positive expressive rates of APE1,PARP1 andBRCA1 in three negative infiltrative ductal breast cancer were 58.3%(35/60),56.7%(34/60)and 35.0%(21/60)respectively.The PARP1 expression in cancer tissue of axillary lymph node metastasis positive was significantly higher than that in cancertissue of axillary lymph node metastasis negative,and the difference was statistically significant(P=0.009);whereas thePARP1 expression had no statistical difference among the onset age,tumor size,tissue differentiation and clinical stages(P>0.05);APE1 was positively correlated with PARP1 expression(r=0.489,P<0.001). The multiple factor Cox regression analysisindicated that the age,axillary lymph node metastasis,poor histological differentiation and APE1 positive expression were theindependent prognostic factors of three negative breast cancer. Conclusion The expression of APE and PARP1 is associatedwith poor prognosis in three-negative breast cancer,and blocking APE1 and PARP1 signaling pathways is expected to become anew therapeutic strategy for three negative infiltrative breast cancer.
引文
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[13] FUNG H,DEMPLE B. A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells[J]. Mol Cell,2005,17(3):463-470.
[2]李挺.乳腺癌分子分型及临床意义[J].中国实用外科杂志,2011,10(3):952.
[3] ISAKOFF SJ. Triple-negative breast cancer;role of specific chemotherapy agents[J]. Cancer J,2010,16(1):53-61.
[4] PAL SK,MORTIMER J. Triple-negative breast cancer;novel therapies and new directions[J]. Maturitas,2009,63(4):269-274.
[5] MARK ROBSON MD,SEOCK-AH,EL?BIETA SENKUS MD,et al.Olaparib for metastatic breast cancer in patients with a germline BRCA Mutation[J]. N Engl J Med,2017,377(23):523-533.
[6] SZABO N. Therapeutic applications of PARP inhibitors;anticancer therapy and beyond[J]. Mol Aspects Med,2013,34(6):153-456.
[7]张诗珩.非小细胞肺癌化疗相关基因标志物表达特征分析[J].重庆医学,2014,43(11):1284-1289.
[8] KROKAN HE,NILSEN H,SKORPEN F,et al. Base excision repair of DNA in mammalian cells[J]. FEBS Lett,2000,476(1/2):73-77.
[9] ANNUNZIATA CM,BATES SE. PARP inhibitors in BRCA1/BRCA2germline mutation carriers with ovarian and breast cancer[J]. F1000 Biol Rep,2010,2.
[10] HAINCE JF,ROULEAU M,HENDZEL MJ,et al. Targeting poly(ADPribosyl)ation;a promising approach in cancer therapy[J]. Trends Mol Med,2005,11(10):456-463.
[11] BAUTE J,DEPICKER A. Base excision repair and its role in maintaining genome stability[J]. Crit Rev Biochem Mol Biol,2008,43(4):239-276.
[12] SUKHANOVA MV,KHODYREVA SN,LEBEDEVA NA,et al. Human base excision repair enzymes apurinic/apyrimidinic endonuclease1(APE1),DNA polymerase beta and poly(ADP-ribose)polymerase 1;interplay between strand-displacement DNA synthesis and proofreading exonuclease activity[J]. Nucleic Acids Res,2005,33(4):1222-1229.
[13] FUNG H,DEMPLE B. A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells[J]. Mol Cell,2005,17(3):463-470.