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Brd4 Protein Linked to Breast Cancer Survival Gene Signature

NEW YORK (GenomeWeb News) – New research is pinpointing a gene that seems to govern a gene signature associated with better breast cancer survival.
 
The gene expression pattern — first identified in mice and later verified in humans — apparently influences tumor growth and metastasis. In research published online this week in the Proceedings of the National Academy of Sciences, investigators from the National Cancer Institute and elsewhere demonstrated that the signature is influenced by one gene coding for a nuclear protein called bromodomain 4 or Brd4.
 
“For the first time in mice, we have a candidate gene for what drives an entire gene signature,” NCI geneticist Kent Hunter, who was senior author on the paper, said in a statement. “This should allow a better understanding of the mechanisms underlying cancer progression in humans.”
 
In typically growing cells, Brd4 is a nuclear protein that’s associated with chromatin. It apparently influences DNA replication and cell cycle progression. Because of its previously identified physical interaction with an invasiveness-suppressing GTPase activating protein called Sipa1, Hunter and his colleagues decided to delve into Brd4’s role in breast cancer.
 
First, the researchers examined Brd4’s potential role in invasiveness. They generated highly metastatic mouse mammary tumor cells transected with a control vector or with a vector expressing Brd4. When Brd4 was present, the cells were less invasive than control cells even though their growth rate remained the same.
 
To determine whether the same was true in an animal model, the researchers implanted both Brd4 expressing and non-expressing tumor cells into female mice and tracked their tumor progression and size after a month. Consistent with the cell line results, the Brd4-expressing mice had fewer metastatic tumors. But unlike the cell lines, they also had smaller tumors overall. The authors speculated that this difference in tumor size in vivo may reflect Brd4’s influence on the tumor microenvironment.
 
In mice Brd4 seemed to regulate the expression of a group of extracellular matrix genes previously classified as a potential metastasis-predictive gene signature. For instance, when they used qPCR to measure gene expression, the team found that five of twelve extracellular-matrix genes showed altered expression in cells expressing vector-borne Brd4.
 
Using Affymetrix GeneChip Mouse Genome 430 2.0 arrays, Hunter and his team also found a Brd4-mediated gene expression profile or signature in mice. Nearly 150 classes of genes seem to be influenced by Brd4 expression — including some related to cellular processes such as cell cycle progression, chromatin structure, cytoskeletal remodeling, cell adhesion, and extracellular matrix functions.
 
They mapped these onto human Affymetrix datasets in the National Center for Biotechnology Information Gene Expression Omnibus as well as the Dutch Rosetta cohort, which used a different microarray platform. Several hundred human genes had expression profiles that were similar to those in Brd4 expressing mouse models. In addition, the level of Brd4 activation could predict survival for all five data sets.
 
It also provided clues about survival in other patient populations such as those whose cancer had not spread to their lymph nodes and those with estrogen-receptor-positive tumors.
 
Still, when the researchers looked at the Brd4 gene signatures associated with improved survival they found overlapping patterns of gene expression. But the patterns weren’t identical. The authors speculate that such differences may exist because of variables such as patient population and microarray platform. Still, they say, the overall Brd4 signature is consistent — and a promising prognostic tool.
 
Though the results are still preliminary, they suggest that this work may help doctors better predict each patient’s breast cancer progression. In addition, the authors noted that they are currently assessing SNP data to determine whether Brd4 polymorphisms also influence breast cancer progression and prognosis.
 
“The results of this study and other work in our laboratory suggests that people with inherited differences in Brd4 and the proteins that it induces have a genetic predisposition for developing cancer metastasis,” Hunter said. “A better understanding of this gene may lead to improved methods of diagnosing and treating cancer.”

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