Six1 is essential to development but is not found in most normal adult cells, according to paper in JCI.

The protein Six1 may play a key role in breast cancer development, according to researchers at the University of Colorado School of Medicine (UCSM). Although this protein is important during development, it is not expressed in the majority of adult cells other than various cancer cells types, including breast cancer cells, they add. 

Two studies from the UCSM group appear in the August 24 edition of The Journal of Clinical Investigation. In the first study expression of human Six1 in mouse breast epithelial cells reportedly resulted in aggressive tumors. The tumors showed signs (including expression of the protein cyclin D1) of a cellular process known as epithelial-to-mesenchymal transition (EMT), which has been linked to the development of metastatic capabilities.

The tumors also had increased numbers of cells with stem/progenitor characteristics. This paper is titled “Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.”

In the second study overexpression of Six1 in human breast cancer cell lines resulted in EMT, in part via the ability of Six1 to increase signaling mediated by a soluble molecule known as TGF-beta. These human cells showed enhanced ability to metastasize when transplanted into mice. The details appear in the paper called “The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling.”

In both studies human data indicated that these phenomena are not restricted to mouse models. First, while Six1 expression has been previously shown to be predictive of poor prognosis in individuals with breast cancer, the UCSM researchers found that co-expression of Six1 and cyclin D1 was an even better predictor of poor prognosis. Second, Six1 expression in human breast cancer tissue correlated with proteins indicative of TGF-beta signaling.

Third, Six1 expression in human breast cancer correlated with shortened time to metastasis and relapse and with shortened overall survival. Finally, the scientists suggest that Six1 expression is probably central to tumor development in other forms of cancer as it correlated with adverse outcomes in numerous other cancers including cancers of the brain, cervix, prostate, colon, kidney, and liver. 

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