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


METHODS
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.
Hayes
Michael J
MJ
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
Thomas
Dafydd
D
Emmons
Agnieszka
A
Giordano
Thomas J
TJ
Kleer
Celina G
CG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation; D019070:Cell Lineage; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D051153:Wnt Proteins / Q000378:metabolism*
D017931:DNA Primers; D051153:Wnt Proteins