β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation
β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation
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DOI：
10.1038/modpathol.2010.205
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发表时间：
2011-02-01
期刊：
影响因子：
7.5
通讯作者：
Reis-Filho, Jorge S.
中科院分区：
文献类型：
--
作者：
Geyer, Felipe C.;Lacroix-Triki, Magali;Reis-Filho, Jorge S.
通过评估其亚细胞定位确定的异常 β-连环蛋白表达构成了 Wnt 信号通路激活的替代标记，并且已在乳腺癌亚群中得到报道。 β-连环蛋白/Wnt 通路激活与临床结果的关联以及导致其在乳腺癌中激活的机制仍然存在争议。本研究的目的是探讨浸润性乳腺癌中β-连环蛋白表达的分布、β-连环蛋白表达与乳腺癌患者临床病理特征和生存之间的相关性，并确定异常的β-连环蛋白表达是否是由CTNNB1（β-连环蛋白编码基因）激活突变驱动的。使用两种抗 β-连环蛋白单克隆抗体对含有 245 个来自统一治疗患者的浸润性乳腺癌的组织微阵列进行免疫组织化学分析。通过直接基因测序对所选样品进行 CTNNB1 外显子 3 突变分析。观察到两种 β-连环蛋白抗体之间存在良好的相关性（Spearman's r > 0.62，P < 0.001）。分别有 31% 和 11% 的病例表现出 β-连环蛋白膜表达和核积聚缺乏/减少。 β-连环蛋白表达的完全缺乏与浸润性小叶癌的组织学类型显着相关。非小叶癌或非小叶 3 级癌的亚组分析显示，β-连环蛋白膜表达的缺乏/减少和/或核积聚与雌激素受体阴性、HER2 基因扩增和过度表达缺失、E-钙粘蛋白表达缺乏/减少以及三阴性和基底样表型肿瘤显着相关。单变量生存分析显示，β-连环蛋白核表达与整个队列中较短的无转移生存期和总生存期之间存在显着相关性。然而，β-连环蛋白核表达并不是多变量分析中结果的独立预测因子。在分析的 28 种选定乳腺癌中未发现 CTNNB1 突变。总之，β-catenin/Wnt 通路激活优先见于三阴性/基底样乳腺癌，与不良临床结果相关，并且不太可能由乳腺癌中的 CTNNB1 突变驱动。现代病理学(2011) 24, 209-231; doi:10.1038/modpathol.2010.205； 2010 年 11 月 12 日在线发布
Aberrant beta-catenin expression as determined by assessment of its subcellular localization constitutes a surrogate marker of Wnt signalling pathway activation and has been reported in a subset of breast cancers. The association of beta-catenin/Wnt pathway activation with clinical outcome and the mechanisms leading to its activation in breast cancers still remain a matter of controversy. The aims of this study were to address the distribution of beta-catenin expression in invasive breast cancers, the correlations between beta-catenin expression and clinicopathological features and survival of breast cancer patients, and to determine whether aberrant beta-catenin expression is driven by CTNNB1 (beta-catenin encoding gene) activating mutations. Immunohistochemistry was performed on a tissue microarray containing 245 invasive breast carcinomas from uniformly treated patients, using two anti-beta-catenin monoclonal antibodies. Selected samples were subjected to CTNNB1 exon 3 mutation analysis by direct gene sequencing. A good correlation between the two beta-catenin antibodies was observed (Spearman's r > 0.62, P < 0.001). Respectively, 31 and 11% of the cases displayed lack/reduction of beta-catenin membranous expression and nuclear accumulation. Complete lack of beta-catenin expression was significantly associated with invasive lobular carcinoma histological type. Subgroup analysis of non-lobular cancers or non-lobular grade 3 carcinomas revealed that lack/reduction of beta-catenin membranous expression and/or nuclear accumulation were significantly associated with oestrogen receptor negativity, absence of HER2 gene amplification and overexpression, lack/reduction of E-cadherin expression and tumours of triple-negative and basal-like phenotype. Univariate survival analysis revealed a significant association between beta-catenin nuclear expression and shorter metastasis-free and overall survival in the whole cohort; however, beta-catenin nuclear expression was not an independent predictor of outcome in multivariate analysis. No CTNNB1 mutations were identified in the 28 selected breast carcinomas analysed. In conclusion, beta-catenin/Wnt pathway activation is preferentially found in triple-negative/basal-like breast carcinomas, is associated with poor clinical outcome and is unlikely to be driven by CTNNB1 mutations in breast cancer. Modern Pathology (2011) 24, 209-231; doi:10.1038/modpathol.2010.205; published online 12 November 2010