Wnt/β-Catenin Pathway Activation Is Enriched in Basal-Like Breast Cancers and Predicts Poor Outcome
Wnt/β-Catenin Pathway Activation Is Enriched in Basal-Like Breast Cancers and Predicts Poor Outcome
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DOI：
10.2353/ajpath.2010.091125
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发表时间：
2010-06-01
影响因子：
6
通讯作者：
Goss, Kathleen H.
中科院分区：
文献类型：
--
作者：
Khramtsov, Andrey I.;Khramtsova, Galina F.;Goss, Kathleen H.
虽然Wnt/β-连环蛋白通路激活已涉及小鼠乳腺癌模型，但关于其在人类乳腺癌中的重要性存在相互矛盾的证据。在这项研究中，浸润性和原位乳腺癌组织微阵列包含管腔A，管腔B，人表皮生长因子受体2（HER 2）（+）/ER-和基底样乳腺癌进行了分析β-连环蛋白亚细胞定位。我们证明了β-连环蛋白的细胞核和胞浆积累，Wnt通路激活的读出，在基底样乳腺癌中富集。相反，在所有乳腺癌亚型中均观察到膜相关β-连环蛋白，其表达随肿瘤进展而降低。此外，β-连环蛋白的核和胞浆定位与基底样表型的其他标志物相关，包括核激素受体和HER 2阴性，细胞角蛋白5/6和波形蛋白表达，以及干细胞富集。重要的是，β-连环蛋白的这种亚细胞定位与不良结局相关，并且在黑人患者的肿瘤中更常见。此外，β-连环蛋白的积累更经常观察到基底样原位癌比其他原位亚型，这表明该途径的激活可能是一个早期事件在基底样肿瘤的发展。总的来说，这些数据表明，Wnt/β-连环蛋白激活是基底细胞样乳腺癌的一个重要特征，并预测较差的总生存期，这表明它可能是这种侵袭性乳腺癌亚型的一个有吸引力的药理学靶点。(Am J Pathol 2010，176：2911-2920; DOI：10.2353/ajpath.2010.091125）
Although Wnt/beta-catenin pathway activation has been implicated in mouse models of breast cancer, there is contradictory evidence regarding its importance in human breast cancer. In this study, invasive and in situ breast cancer tissue microarrays containing luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)(+)/ER- and basal-like breast cancers were analyzed for beta-catenin subcellular localization. We demonstrate that nuclear and cytosolic accumulation of beta-catenin, a read-out of Wnt pathway activation, was enriched in basal-like breast cancers. In contrast, membrane-associated beta-catenin was observed in all breast cancer subtypes, and its expression decreased with tumor progression. Moreover, nuclear and cytosolic localization of beta-catenin was associated with other markers of the basal-like phenotype, including nuclear hormone receptor and HER2 negativity, cytokeratin 5/6 and vimentin expression, and stem cell enrichment. Importantly, this subcellular localization of beta-catenin was associated with a poor outcome and is more frequently observed in tumors from black patients. In addition, beta-catenin accumulation was more often observed in basal-like in situ carcinomas than other in situ subtypes, suggesting that activation of this pathway might be an early event in basal-like tumor development. Collectively, these data indicate that Wnt/beta-catenin activation is an important feature of basal-like breast cancers and is predictive of worse overall survival, suggesting that it may be an attractive pharmacological target for this aggressive breast cancer subtype. (Am J Pathol 2010, 176:2911-2920; DOI: 10.2353/ajpath.2010.091125)