Murria Rosa, Palanca Sarai, de Juan Inmaculada, Alenda Cristina, Egoavil Cecilia, Seguí Francisco J, García-Casado Zaida, Juan María J, Sánchez Ana B, Segura Ángel, Santaballa Ana, Chirivella Isabel, Llop Marta, Pérez Gema, Barragán Eva, Salas Dolores, Bolufer Pascual
Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe Valencia, Spain.
Department of Pathology, University General Hospital Alicante, Spain.
Am J Cancer Res. 2015 Jun 15;5(7):2330-43. eCollection 2015.
This study aims to identify the profile of immunohistochemical (IHC) parameters, copy number aberrations (CNAs) and epigenetic alterations [promoter methylation (PM) and miR expression] related to hereditary (H) and triple negative (TN) breast cancer (BC). This profile could be of relevance for guiding tumor response to treatment with targeting therapy. The study comprises 278 formalin fixed paraffin-embedded BCs divided into two groups: H group, including 88 hereditary BC (HBC) and 190 non hereditary (NHBC), and TN group, containing 79 TNBC and 187 non TNBC (NTNBC). We assessed IHC parameters (Ki67, ER, PR, HER2, CK5/6, CK18 and Cadherin-E), CNA of 20 BC related genes, and PM of 24 tumor suppressor genes employing MLPA/MS-MLPA (MRC Holland, Amsterdam). MiR-4417, miR-423-3p, miR-590-5p and miR-187-3p expression was assessed by quantitative RT-PCR (Applied Biosystems). Binary logistic regression was applied to select the parameters that better differentiate the HBC or TN groups. For HBC we found that, ER expression, ERBB2 CNA and PM in RASSF1 and TIMP3 were associated with NHBC whereas; MYC and AURKA CNA were linked to HBC. For TNBC, we found that CDC6 CNA, GSTP1 and RASSF1 PM and miR-423-3p hyperexpression were characteristic of NTNBC, while MYC aberrations, BRCA1 hypermethylation and miR-590-5p and miR-4417 hyperexpression were more indicative of TNBC. The selected markers allow establishing BC subtypes, which are characterized by showing similar etiopathogenetic mechanisms, some of them being molecular targets for known drugs or possible molecular targets. These results could be the basis to implement a personalized therapy.
本研究旨在确定与遗传性（H）和三阴性（TN）乳腺癌（BC）相关的免疫组化（IHC）参数、拷贝数变异（CNA）和表观遗传改变[启动子甲基化（PM）和miR表达]的特征。该特征可能与指导肿瘤对靶向治疗的反应相关。该研究包括278例福尔马林固定石蜡包埋的乳腺癌，分为两组：H组，包括88例遗传性乳腺癌（HBC）和190例非遗传性（NHBC）；TN组，包含79例三阴性乳腺癌（TNBC）和187例非三阴性乳腺癌（NTNBC）。我们评估了IHC参数（Ki67、ER、PR、HER2、CK5/6、CK18和E-钙黏蛋白）、20个与乳腺癌相关基因的CNA以及采用多重连接探针扩增技术/甲基化特异性多重连接探针扩增技术（MRC Holland，阿姆斯特丹）检测的24个抑癌基因的PM。通过定量逆转录-聚合酶链反应（Applied Biosystems）评估miR-4417、miR-423-3p、miR-590-5p和miR-187-3p的表达。应用二元逻辑回归来选择能更好区分HBC或TN组的参数。对于HBC，我们发现ER表达、ERBB2 CNA以及RASSF1和TIMP3中的PM与NHBC相关，而MYC和AURKA CNA与HBC相关。对于TNBC，我们发现CDC6 CNA、GSTP1和RASSF1 PM以及miR-423-3p高表达是NTNBC的特征，而MYC异常、BRCA1高甲基化以及miR-590-5p和miR-4417高表达更提示TNBC。所选标志物有助于确定乳腺癌亚型，其特征是显示出相似的病因发病机制，其中一些是已知药物的分子靶点或可能的分子靶点。这些结果可为实施个性化治疗奠定基础。
