Université Clermont Auvergne, Centre Jean Perrin, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, France.
Département d'Oncogénétique, Centre Jean Perrin, F-63000 Clermont Ferrand, France.
Int J Med Sci. 2018 Jan 1;15(1):46-58. doi: 10.7150/ijms.20508. eCollection 2018.
Basal-like breast cancers are among the most aggressive cancers and effective targeted therapies are still missing. In order to identify new therapeutic targets, we performed Methyl-Seq and RNA-Seq of 10 breast cancer cell lines with different phenotypes. We confirmed that breast cancer subtypes cluster the RNA-Seq data but not the Methyl-Seq data. Basal-like tumor hypermethylated phenotype was not confirmed in our study but RNA-Seq analysis allowed to identify 77 genes significantly overexpressed in basal-like breast cancer cell lines. Among them, 48 were overexpressed in triple negative breast cancers of TCGA data. Some molecular functions were overrepresented in this candidate gene list. Genes involved in antioxydation, such as SOD1, MGST3 and PRDX or cadherin-binding genes, such as PFN1, ITGB1 and ANXA1, could thus be considered as basal like breast cancer biomarkers. We then sought if these genes were linked to BRCA1, since this gene is often inactivated in basal-like breast cancers. Nine genes were identified overexpressed in both basal-like breast cancer cells and BRCA1 mutated cells. Amongst them, at least 3 genes code for proteins implicated in epithelial cell migration and epithelial to mesenchymal transition (VIM, ITGB1 and RhoA). Our study provided several potential therapeutic targets for triple negative and BRCA1 mutated breast cancers. It seems that migration and mesenchymal properties acquisition of basal-like breast cancer cells is a key functional pathway in these tumors with a high metastatic potential.
基底样乳腺癌是最具侵袭性的癌症之一，目前仍缺乏有效的靶向治疗方法。为了确定新的治疗靶点，我们对 10 种具有不同表型的乳腺癌细胞系进行了甲基化测序和 RNA 测序。我们证实，乳腺癌亚型可以对 RNA-Seq 数据进行聚类，但不能对 Methyl-Seq 数据进行聚类。在我们的研究中，基底样肿瘤高甲基化表型未得到证实，但 RNA-Seq 分析可以识别出 77 个在基底样乳腺癌细胞系中过表达的基因。其中，48 个在 TCGA 数据的三阴性乳腺癌中过表达。在这个候选基因列表中，一些分子功能被过度表达。涉及抗氧化的基因，如 SOD1、MGST3 和 PRDX，或钙粘蛋白结合基因，如 PFN1、ITGB1 和 ANXA1，因此可以被认为是基底样乳腺癌的生物标志物。然后，我们试图确定这些基因是否与 BRCA1 有关，因为该基因在基底样乳腺癌中经常失活。在基底样乳腺癌细胞和 BRCA1 突变细胞中，有 9 个基因被鉴定为过表达。其中，至少有 3 个基因编码的蛋白质与上皮细胞迁移和上皮-间充质转化有关（VIM、ITGB1 和 RhoA）。我们的研究为三阴性和 BRCA1 突变型乳腺癌提供了几个潜在的治疗靶点。基底样乳腺癌细胞的迁移和间充质特性的获得似乎是这些具有高转移潜能的肿瘤的一个关键功能途径。
