Ccn6, also known as WISP3, is a gene encoding a matrix-associated protein of the CCN family. It has regulatory roles in development and cancer, with a conserved multimodular structure similar to other CCN proteins. Ccn6 is involved in pathways such as epithelial-to-mesenchymal transitions (EMT) and Notch signaling, and is of great biological importance in processes like maintaining cell phenotypes and in mitochondrial function [1,2]. Genetic models, especially knockout mouse models, are valuable for studying its functions.

In breast cancer, Ccn6 is a tumor suppressor. Conditional, mammary epithelial-cell specific ccn6 (wisp3) knockout mice develop invasive high-grade mammary carcinomas that recapitulate human spindle cell metaplastic carcinomas. This indicates that Ccn6 loss is associated with aggressive breast cancers, such as metaplastic carcinomas where its expression is reduced. Ccn6 suppresses metaplastic breast carcinoma by antagonizing Wnt/β-Catenin signaling to inhibit EZH2-driven EMT. In these carcinomas, Ccn6 interacts with Wnt receptors to block β-catenin/TCF-mediated transcription, and EZH2, a target of this signaling, can be a therapeutic target when Ccn6 is deficient [1,3].

In summary, Ccn6 is crucial for maintaining normal biological functions, especially in breast tissue where it acts as a tumor suppressor. The use of ccn6 knockout mouse models has been instrumental in revealing its role in breast cancer, particularly in metaplastic carcinomas, highlighting potential therapeutic strategies targeting the pathways affected by Ccn6 deficiency.

References:

1. Tran, Mai N, Kleer, Celina G. 2018. Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas. In Journal of cell communication and signaling, 12, 13-19. doi:10.1007/s12079-018-0451-9. https://pubmed.ncbi.nlm.nih.gov/29357008/

2. Leask, Andrew. 2016. CCN6: a modulator of breast cancer progression. In Journal of cell communication and signaling, 10, 163-4. doi:10.1007/s12079-016-0321-2. https://pubmed.ncbi.nlm.nih.gov/27086280/

3. Gonzalez, Maria E, Brophy, Bryce, Eido, Ahmad, Fearon, Eric R, Kleer, Celina G. . CCN6 Suppresses Metaplastic Breast Carcinoma by Antagonizing Wnt/β-Catenin Signaling to Inhibit EZH2-Driven EMT. In Cancer research, 84, 3235-3249. doi:10.1158/0008-5472.CAN-23-4054. https://pubmed.ncbi.nlm.nih.gov/39024552/