Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast.
Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast.
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Wnt途径基因的遗传变化是乳房化生癌中的常见事件。
DOI：
10.1158/1078-0432.ccr-07-4379
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发表时间：
2008-07-01
期刊：
影响因子：
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通讯作者：
Kleer CG
中科院分区：
文献类型：
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作者：
Hayes MJ;Thomas D;Emmons A;Giordano TJ;Kleer CG
化生性癌是一种独特的浸润性乳腺癌，具有异常的非腺体分化，可以是梭形、鳞状或软骨样。由于缺乏对其分子病因学的认识，有效的治疗方法有限。鉴于Wnt通路在细胞命运和乳腺癌发展中的作用，我们假设该通路的缺陷可能有助于化生性癌的发展。在36例原发性化生性癌中，我们采用免疫组织化学（IHC）检测β-连环蛋白表达和定位，并对CTNNB 1（编码β-连环蛋白）、APC、WISP 3、AXIN 1和AXIN 2基因进行突变分析，全面确定β-连环蛋白和Wnt通路失调的患病率和潜在机制。通过IHC，正常β-连环蛋白被视为膜染色，并且当> 5%的肿瘤细胞具有核或胞质积聚或膜染色减少时，它是异常的。通过IHC，36例病例中的33例（92%）存在异常β-连环蛋白，揭示了Wnt通路的失调。在27例可用于突变分析的肿瘤中的7例（25.9%）中检测到CTNNB 1错义突变。所有突变都影响β-连环蛋白的NH 2-末端结构域，可能使突变蛋白抵抗降解。27例肿瘤中有2例（7.4%）存在APC突变，5例（18.5%）存在WISP 3移码突变。未发现AXIN 1或AXIN 2突变。Wnt信号通路的激活在这种特殊的乳腺癌亚型中很常见。CTNNB 1、APC和WISP 3突变的发现可能为乳腺化生癌患者带来新的治疗方法。
Metaplastic carcinomas are distinct invasive breast carcinomas with aberrant non-glandular differentiation, which may be spindle, squamous, or chondroid. The limited effective treatments result from the lack of knowledge of its molecular etiology. Given the role of the Wnt pathway in cell fate and in the development of breast cancer, we hypothesized that defects in this pathway may contribute to the development of metaplastic carcinomas. In 36 primary metaplastic carcinomas we comprehensively determined the prevalence of and mechanism underlying β-catenin and Wnt pathway deregulation using immunohistochemistry (IHC) for β-catenin expression and localization, and mutational analysis for CTNNB1 (encoding β-catenin), APC, WISP3, AXIN1, and AXIN2 genes. By IHC, normal β-catenin was seen as membrane staining, and it was aberrant when > 5% of tumor cells had nuclear or cytoplasmic accumulation or reduced membrane staining. By IHC aberrant β-catenin was present in 33 of 36 (92%) cases, revealing deregulation of the Wnt pathway. CTNNB1 missense mutations were detected in 7 of 27 (25.9 %) tumors available for mutation analyses. All mutations affected the NH2-terminal domain of β-catenin, presumably rendering the mutant protein resistant to degradation. Two of 27 tumors (7.4 %) had mutations of APC, and 5 (18.5 %) carried a frame shift mutation of WISP3. No AXIN1 or AXIN2 mutations were found. Activation of the Wnt signaling pathway is common in this specific subtype of breast carcinoma. The discovery of CTNNB1, APC, and WISP3 mutations may result in new treatments for patients with metaplastic carcinomas of the breast.