Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast

Abstract

Purpose: 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.

Design: In 36 primary metaplastic carcinomas, we comprehensively determined the prevalence of and mechanism underlying beta-catenin and Wnt pathway deregulation using immunohistochemistry for beta-catenin expression and localization and mutational analysis for CTNNB1 (encoding beta-catenin), APC, WISP3, AXIN1, and AXIN2 genes. By immunohistochemistry, normal beta-catenin was seen as membrane staining, and it was aberrant when >5% of tumor cells had nuclear or cytoplasmic accumulation or reduced membrane staining.

Results: By immunohistochemistry, aberrant beta-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 NH(2)-terminal domain of beta-catenin, presumably rendering the mutant protein resistant to degradation. Two of 27 (7.4%) tumors had mutations of APC, and 5 (18.5%) carried a frame shift mutation of WISP3. No AXIN1 or AXIN2 mutations were found.

Conclusions: 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.

Figure 1. Immunohistochemical staining of β-catenin in metaplastic carcinomas of the breast, and representative mutations on CTNNB1, APC, and WISP3 genes

A, metaplastic carcinoma with glandular and spindle cell differentiation; B, same tumor showing accumulation of β-catenin in a region of the tumor with spindle cell differentiation (arrow). Note the membrane associated β-catenin immunoreactivity in the epithelial component; C, metaplastic carcinoma with chondroid differentiation; D, this tumor shows prominent nuclear and cytoplasmic immunoreactivity for β-catenin in the vast majority of neoplastic cells; E, metaplastic carcinoma with glandular elements and highly atypical spindle cells; F, note the membranous expression β-catenin protein in the glandular elements (bottom right) in stark contrast to the nearly absent β-catenin expression in the malignant spindle cells; G, metaplastic carcinoma with squamous differentiation; H, this tumor shows membrane-associated localization of β-catenin immunoreactivity without detectable nuclear immunoreactivity; I, representative examples of CTNNB1, WISP3, and APC gene mutations found in these tumors. For the APC mutation, the G to A results in a stop codon. All pictures are 400x magnification.