Tapia Teresa, Smalley Susan V, Kohen Paulina, Muñoz Alex, Solis Luisa M, Corvalan Alejandro, Faundez Paola, Devoto Luigi, Camus Mauricio, Alvarez Manuel, Carvallo Pilar
Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Epigenetics. 2008 May-Jun;3(3):157-63. doi: 10.4161/epi.3.3.6387. Epub 2008 Jun 5.
Germline mutations in BRCA1 account for a low proportion of hereditary cases in diverse populations. Several efforts have been made to find new genes involved in the inheritance of breast cancer with no success until today. The participation of BRCA1 in the development of breast cancer has been proposed in several studies where hypermethylation of its promoter and a decrease in expression has been reported for sporadic cases and one study on familial cases. To explore the participation of BRCA1 in hereditary carcinogenesis through a different mechanism than the inheritance of germline mutations, we studied the methylation status of its promoter in breast tumors, from patients previously screened for BRCA1/BRCA2 germline mutations. We also determined the presence of the BRCA1 protein in these tumors and correlated both events with tumor grade, hormone receptors and ERBB2 presence. Promoter hypermethylation of the BRCA1 gene was detected in 51% of our biopsies, among which 67% did not express the respective protein. This result leads us to suggest that hypermethylation could be considered as an inactivating mechanism for BRCA1 expression, either as a first or second hit. Moreover, a number of biopsies with absence of expression on BRCA1 showed negative detection of estrogen and progesterone receptors, a similar phenotype to BRCA1 mutated breast tumors.
在不同人群中，BRCA1基因的种系突变在遗传性病例中所占比例较低。此前人们曾多次尝试寻找与乳腺癌遗传相关的新基因，但至今均未成功。多项研究提出BRCA1参与乳腺癌的发生发展，其中有研究报道散发性病例以及一项家族性病例研究中，BRCA1启动子发生高甲基化且表达降低。为了探究BRCA1通过不同于种系突变遗传的机制参与遗传性致癌作用，我们研究了先前已筛查BRCA1/BRCA2种系突变的乳腺癌患者肿瘤组织中BRCA1启动子的甲基化状态。我们还测定了这些肿瘤组织中BRCA1蛋白的表达情况，并将这两个指标与肿瘤分级、激素受体及ERBB2表达情况进行关联分析。在我们的活检样本中，51%检测到BRCA1基因启动子高甲基化，其中67%未表达相应蛋白。这一结果提示我们，高甲基化可能被视为BRCA1表达的一种失活机制，无论是作为首次还是二次打击。此外，一些BRCA1无表达的活检样本显示雌激素和孕激素受体检测呈阴性，这与BRCA1突变的乳腺肿瘤具有相似的表型。
