MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Metaplastic breast carcinoma (MBC) is an aggressive cancer subtype.
• The molecular drivers of MBC, particularly epithelial to mesenchymal transition (EMT), remain unclear.
• CCN6 (WISP3) is a secreted protein implicated in various cellular processes.

Purpose of the Study:

• To investigate the role of CCN6 in metaplastic breast carcinoma pathogenesis.
• To establish a preclinical model for studying MBC with EMT.
• To identify molecular similarities between mouse models and human MBC.

Main Methods:

• Generated a conditional knockout mouse model for Ccn6 deletion in mammary epithelium (Ccn6^fl/fl;MMTV-Cre).
• Analyzed mammary gland development, involution, and tumor formation in the mouse model.
• Performed global gene expression profiling of mouse mammary carcinomas.
• Compared gene expression data with human metaplastic carcinoma signatures.

Main Results:

• CCN6 was significantly downregulated in human spindle cell metaplastic breast carcinoma.
• Ccn6 deletion in mice led to severe ductal branching defects and abnormal involution.
• Ccn6-deficient mice developed invasive, high-grade mammary carcinomas exhibiting EMT, histologically resembling human MBC.
• Identified a significant overlap of 87 genes between mouse and human metaplastic carcinomas, including key regulators of epithelial morphogenesis.

Conclusions:

• Ccn6 deletion plays a causal role in the development of metaplastic breast carcinomas with EMT.
• The established mouse model recapitulates key histological and molecular features of human MBC.
• This model provides a platform for investigating diagnostic and therapeutic targets for metaplastic breast carcinoma.