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Human Breast Cancer Hit For Six: Key Role For Six1 In Tumor Development And Metastasis

Date:
August 31, 2009
Source:
Journal of Clinical Investigation
Summary:
Researchers have provided new insight into breast cancer development using mouse models and analysis of human cells, implicating the protein Six1 as central to this process.

Heide Ford and colleagues, at the University of Colorado School of Medicine, Aurora, have provided new insight into breast cancer development using mouse models and analysis of human cells, implicating the protein Six1 as central to this process, according to research to be published in the August 24 issue of the Journal of Clinical Investigation.

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Six1, a protein that plays a central role in development, is not expressed in the majority of adult cells other than cancer cells of several types, including breast cancer cells. In the first of two studies from the Ford laboratory, expression of human Six1 in mouse breast gland cells known as epithelial cells resulted in aggressive tumors. The tumors showed signs (including expression of the protein cyclin D1) of a cellular process known as EMT, which has been linked to the development of metastatic capability, and had increased numbers of cells with stem/progenitor characteristics, cells that have been linked to increased tumor progression and resistance to many therapies. 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. Importantly, these human cells showed enhanced ability to metastasize when transplanted into mice.

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, Ford and colleagues found that coexpression 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 authors 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.

In an accompanying commentary, Derek Radisky, at the Mayo Clinic, Jacksonville, discusses how the two papers compliment each other to provide new detailed understanding of the mechanisms by which Six1 promotes tumor development and metastasis. Information that it might be possible to translate for clinical benefit.


Story Source:

The above story is based on materials provided by Journal of Clinical Investigation. Note: Materials may be edited for content and length.


Journal References:

  1. McCoy et al. Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI37691
  2. Micalizzi et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-β signaling. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI37815
  3. Derek C. Radisky. Defining a role for the homeoprotein Six1 in EMT and mammary tumorigenesis. Journal of Clinical Investigation, 2009; DOI: 10.1172/JCI40555

Cite This Page:

Journal of Clinical Investigation. "Human Breast Cancer Hit For Six: Key Role For Six1 In Tumor Development And Metastasis." ScienceDaily. ScienceDaily, 31 August 2009. <www.sciencedaily.com/releases/2009/08/090825084948.htm>.
Journal of Clinical Investigation. (2009, August 31). Human Breast Cancer Hit For Six: Key Role For Six1 In Tumor Development And Metastasis. ScienceDaily. Retrieved March 5, 2015 from www.sciencedaily.com/releases/2009/08/090825084948.htm
Journal of Clinical Investigation. "Human Breast Cancer Hit For Six: Key Role For Six1 In Tumor Development And Metastasis." ScienceDaily. www.sciencedaily.com/releases/2009/08/090825084948.htm (accessed March 5, 2015).

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