High RAD51 mRNA expression characterize estrogen receptor-positive/progesteron receptor-negative breast cancer and is associated with patient's outcome
High RAD51 mRNA expression characterize estrogen receptor-positive/progesteron receptor-negative breast cancer and is associated with patient's outcome
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DOI：
10.1002/ijc.25736
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发表时间：
2011-08-01
影响因子：
6.4
通讯作者：
Parrella, Paola
中科院分区：
文献类型：
--
作者：
Barbano, Raffaela;Copetti, Massimiliano;Parrella, Paola
DNA双链断裂（DSB）修复基因的突变参与了遗传性乳腺肿瘤的发病机制，但该通路的缺陷是否在散发性乳腺癌中起作用尚不清楚。在本研究中，我们通过逆转录定量聚合酶链反应，初步测定了20例乳腺癌配对正常组织和癌样中15个DSB相关基因的mRNA表达，并将其分类为同质簇。G22P1/ku70、ATR和RAD51基因在聚类分析识别的三个分支中存在差异表达。特别地，我们发现了一个以高RAD51 mRNA水平和雌激素受体（ER）阳性/孕激素受体（PR）阴性表型为特征的乳腺癌亚组。这一结果通过分析来自扩展乳腺癌队列的配对正常和肿瘤标本（n = 75）的G22P1/ku70， ATR和RAD51 mRNA水平得到证实。RAD51 mRNA水平与PR状态呈负相关（p = 0.02），并且在er阳性/PR阴性肿瘤中检测到最高水平（p = 0.03）。组织芯片RAD51免疫染色证实了RAD51高表达与PR阴性状态呈负相关（p = 0.002），以及与er阳性/PR阴性表型相关（p = 0.003）。有趣的是，对295例乳腺癌的微阵列表达数据的分析表明，RAD51 mRNA表达的增加与肿瘤复发、远处转移和最差总生存率的增加相关（p = 0.015、p = 0.009和p = 0.013）。我们的研究结果表明，RAD51的表达测定有助于更好地对乳腺肿瘤进行分子分类，并可能成为评估乳腺癌患者术后辅助治疗的新工具。
Mutations in DNA double-strand breaks (DSB) repair genes are involved in the pathogenesis of hereditary mammary tumors, it is, however, still unclear whether defects in this pathway may play a role in sporadic breast cancer. In this study, we initially determined mRNA expression of 15 DSB related genes by reverse transcription quantitative polymerase chain reaction in paired normal tissue and cancer specimen from 20 breast cancer cases to classify them into homogeneous clusters. G22P1/ku70, ATR and RAD51 genes were differentially expressed in the three branches recognized by clustering analysis. In particular, a breast cancer subgroup characterized by high RAD51 mRNA levels and estrogen receptor (ER)-positive/progesteron receptor (PR)-negative phenotype was identified. This result was confirmed by the analysis of G22P1/ku70, ATR and RAD51 mRNA levels on paired normal and tumor specimens from an extended breast cancer cohort (n = 75). RAD51 mRNA levels were inversely associated with PR status (p = 0.02) and the highest levels were, indeed, detected in ER-positive/PR-negative tumors (p = 0.03). RAD51 immunostaining of a tissue microarray confirmed the inverse relationship between high RAD51 expression and negative PR status (p = 0.002), as well as, the association with ER-positive/PR-negative phenotype (p = 0.003). Interestingly, the analysis of microarray expression data from 295 breast cancers indicate that RAD51 increased mRNA expression is associated with higher risk of tumor relapse, distant metastases and worst overall survival (p = 0.015, p = 0.009 and p = 0.013 respectively). Our results suggest that RAD51 expression determination could contribute to a better molecular classification of mammary tumors and may represent a novel tool for evaluating postoperative adjuvant therapy for breast cancer patients.