Cancer Aggressiveness Linked to Lack of COMMD1 Protein Activity

Cancer researchers have linked low levels of the COMMD1 (copper metabolism (Murr1) domain containing 1) protein to increased cancer aggressiveness and tendency to metastasize.

COMMD1 has been shown to inhibit both NF-kappaB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) and HIF (hypoxia inducible factor) mediated gene expression. NF-kappaB and HIF are transcription factors that have been shown to play a role in promoting tumor growth, survival, and invasion.

In the current study, investigators at the University of Texas Southwestern Medical Center (Dallas, USA) studied the role of COMMD1 expression in human cancers. They reported in the June 2010 issue of the Journal of Clinical Investigation that analysis of COMMD1 levels in 63 patients with endometrial cancer showed that those whose tumors had the lowest levels of COMMD1 had the worst clinical outcomes. Experiments in animals revealed that direct repression of the COMMD1 gene in human cell lines led to increased tumor invasion in a chick xenograft model, while increased COMMD1 gene expression in mouse melanoma cells led to decreased lung metastasis in a mouse model.

Decreased COMMD1 gene expression also correlated with increased expression of genes known to promote cancer cell invasiveness, including direct targets of HIF. At the molecular level the investigators found that COMMD1 inhibited HIF-mediated gene expression by binding directly to the amino terminus of HIF-1-alpha, preventing its dimerization with HIF-1-beta and subsequent DNA binding and transcriptional activation.

"This is the first study that clearly links COMMD1 to human disease and substantiates what we would have expected based on the prior work we have done on this protein,” said senior author Dr. Ezra Burstein, assistant professor of internal medicine and molecular biology at the University of Texas Southwestern Medical Center. "COMMD1 is yet another player in the very important and complicated cancer invasion process.”

"Further down the line we could create a drug that would bring COMMD1 protein levels back to normal, or even above normal, in the tumor to hopefully affect cancer cell invasion,” said Dr. Ezra Burstein. "If the cancer cells have already started invading other organs, maybe further invasion would be halted or even regressed.”

Related Links:
University of Texas Southwestern Medical Center