Data from Genetic Changes of Wnt Pathway Genes Are Common Events in Metaplastic Carcinomas of the Breast

<div>Abstract<p><b>Purpose:</b> Metaplastic carcinomas are distinct invasive breast carcinomas with aberrant nonglandular 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.</p><p><b>Design:</b> In 36 primary metaplastic carcinomas, we comprehensively determined the prevalence of and mechanism underlying β-catenin and Wnt pathway deregulation using immunohistochemistry for β-catenin expression and localization and mutational analysis for <i>CTNNB1</i> (encoding β-catenin), <i>APC, WISP3, AXIN1</i>, and <i>AXIN2</i> genes. By immunohistochemistry, 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.</p><p><b>Results:</b> By immunohistochemistry, aberrant β-catenin was present in 33 of 36 (92%) cases, revealing deregulation of the Wnt pathway. <i>CTNNB1</i> 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 (7.4%) tumors had mutations of <i>APC</i>, and 5 (18.5%) carried a frame shift mutation of <i>WISP3.</i> No <i>AXIN1</i> or <i>AXIN2</i> mutations were found.</p><p><b>Conclusions:</b> Activation of the Wnt signaling pathway is common in this specific subtype of breast carcinoma. The discovery of <i>CTNNB1, APC</i>, and <i>WISP3</i> mutations may result in new treatments for patients with metaplastic carcinomas of the breast.</p></div>