Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas

Located at 6q22–23, Ccn6 (WISP3) encodes for a matrix-associated protein of the CCN family, characterized by regulatory, rather than structural, roles in development and cancer. CCN6, the least studied member of the CCN family, shares the conserved multimodular structure of CCN proteins, as well as...

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Bibliographic Details
Published in:Journal of cell communication and signaling 2018-03, Vol.12 (1), p.13-19
Main Authors: Tran, Mai N., Kleer, Celina G.
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Breast cancer
Breast carcinoma
CCN6
Cell Biology
EMT
Epithelial to mesenchymal
Inflammation
Invasiveness
Knockout mouse
Life Sciences
Mammary gland
Mesenchyme
Metaplastic
MMTV‐cre
mRNA
Proteins
Review
Spindle cell
Stem cells
Tumor suppressor genes
WISP3
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Summary:Located at 6q22–23, Ccn6 (WISP3) encodes for a matrix-associated protein of the CCN family, characterized by regulatory, rather than structural, roles in development and cancer. CCN6, the least studied member of the CCN family, shares the conserved multimodular structure of CCN proteins, as well as their tissue and cell-type specific functions. In the breast, CCN6 is a critical regulator of epithelial-to-mesenchymal transitions (EMT) and tumor initiating cells. Studies using human breast cancer tissue samples demonstrated that CCN6 messenger RNA and protein are expressed in normal breast epithelia but reduced or lost in aggressive breast cancer phenotypes, especially inflammatory breast cancer and metaplastic carcinomas. Metaplastic carcinomas are mesenchymal-like triple negative breast carcinomas, enriched for markers of EMT and stemness. RNAseq analyses of the TCGA Breast Cancer cohort show reduced CCN6 expression in approximately 50% of metaplastic carcinomas compared to normal breast. Our group identified frameshift mutations of Ccn6 in a subset of human metaplastic breast carcinoma. Importantly, conditional, mammary epithelial-cell specific ccn6 ( wisp3 ) knockout mice develop invasive high-grade mammary carcinomas that recapitulate human spindle cell metaplastic carcinomas, demonstrating a tumor suppressor function for ccn6 . Our studies on CCN6 functions in metaplastic carcinoma highlight the potential of CCN6 as a novel therapeutic approach for this specific type of breast cancer.
ISSN:1873-9601
1873-961X
DOI:10.1007/s12079-018-0451-9