Jacot William, Thezenas Simon, Senal Romain, Viglianti Cathy, Laberenne Anne-Claire, Lopez-Crapez Evelyne, Bibeau Frédéric, Bleuse Jean-Pierre, Romieu Gilles, Lamy Pierre-Jean
Department of Medical Oncology, Montpellier Cancer Institute, Montpellier, France.
BMC Cancer. 2013 Nov 5;13:523. doi: 10.1186/1471-2407-13-523.
Poly(adenosine diphosphate-ribose) polymerase 1 (PARP-1) and the balance between BRCA1 and 53BP1 play a key role in the DNA repair and cell stress response. PARP inhibitors show promising clinical activity in metastatic triple negative (TN) or BRCA-mutated breast cancer. However, a comprehensive analysis of PARP-1 activity, BRCA1 promoter methylation and 53BP1 expression in tumours without known BRCA1 mutation has not yet been carried out.
We investigated cytosolic PARP-1 activity, 53BP1 protein levels and BRCA1 promoter methylation in 155 surgical breast tumour samples from patients without familial breast cancer history or known BRCA1 mutations who were treated between January 2006 and November 2009 and evaluated their statistical association with classical predictive and prognostic factors.
The mitotic count score was the only parameter clearly associated with PARP-1 activity. BRCA1 promoter hypermethylation (15.4% of all cancers) was significantly associated with uPA and PAI-1 levels, tumour grade, mitotic count score, hormone receptor and HER2 negative status and TN profile (29% of TN tumours showed BRCA1 promoter hypermethylation compared to 5% of grade II-III hormone receptor-positive/HER2-negative and 2% of HER2-positive tumours). No statistical association was found between BRCA1 promoter hypermethylation and PARP-1 activity. High 53BP1 protein levels correlated with lymph node positivity, hormone receptor positivity, molecular grouping, unmethylated BRCA1 promoter and PARP-1 activity. In TN tumours, BRCA1 promoter methylation was only marginally associated with age, PARP-1 activity was not associated with any of the tested clinico-pathological factors and high 53BP1 protein levels were significantly associated with lymph node positivity. Only 3 of the 14 TN tumours with BRCA1 promoter hypermethylation presented high 53BP1 protein levels.
Breast cancers that harbour simultaneously high 53BP1 protein level and BRCA1 promoter hypermethylation and are the putative target population of drugs targeting DNA repair appear to be restricted to a small subgroup of TN tumours.
聚（腺苷二磷酸 - 核糖）聚合酶1（PARP - 1）以及BRCA1和53BP1之间的平衡在DNA修复和细胞应激反应中起关键作用。PARP抑制剂在转移性三阴性（TN）或BRCA突变型乳腺癌中显示出有前景的临床活性。然而，尚未对无已知BRCA1突变的肿瘤中PARP - 1活性、BRCA1启动子甲基化和53BP1表达进行全面分析。
我们研究了2006年1月至2009年11月期间接受治疗的155例无家族性乳腺癌病史或已知BRCA1突变的手术切除乳腺肿瘤样本中的胞质PARP - 1活性、53BP1蛋白水平和BRCA1启动子甲基化，并评估了它们与经典预测和预后因素的统计学关联。
有丝分裂计数评分是唯一与PARP - 1活性明显相关的参数。BRCA1启动子高甲基化（占所有癌症的15.4%）与尿激酶型纤溶酶原激活剂（uPA）和纤溶酶原激活物抑制剂1（PAI - 1）水平、肿瘤分级、有丝分裂计数评分、激素受体和HER2阴性状态以及TN特征显著相关（29%的TN肿瘤显示BRCA1启动子高甲基化，相比之下，II - III级激素受体阳性/HER2阴性肿瘤为5%，HER2阳性肿瘤为2%）。未发现BRCA1启动子高甲基化与PARP - 1活性之间存在统计学关联。高53BP1蛋白水平与淋巴结阳性、激素受体阳性、分子分型、未甲基化的BRCA1启动子和PARP - 1活性相关。在TN肿瘤中，BRCA1启动子甲基化仅与年龄有微弱关联，PARP - 1活性与任何测试的临床病理因素均无关联，高53BP1蛋白水平与淋巴结阳性显著相关。在14例BRCA1启动子高甲基化的TN肿瘤中，只有3例呈现高53BP1蛋白水平。
同时具有高53BP1蛋白水平和BRCA1启动子高甲基化且可能是DNA修复靶向药物目标人群的乳腺癌似乎仅限于TN肿瘤的一个小亚组。
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