Breast Cancer Metastasis: Do Variations in Inherited Genes Make a Difference?

A network of inherited gene polymorphisms — slightly different forms of the same gene — may predict whether a breast cancer will metastasize, according to new studies in mice by geneticist Kent Hunter, Ph.D. , and colleagues at the National Cancer Institute. The most recent study, published in April in the Proceedings of the National Academy of Sciences, focused on one gene called Brd4, which the scientists believe may be one of the main drivers in a network of breast can cer metastasis – related genes. Found in mice and humans, the gene is normally involved in cell proliferation, cell cycle progression, and DNA replication, all of which can go awry in metastasis. It also interacts with another important gene called Sipa1, which is already known to infl uence breast tumor invasiveness in mice. The researchers concluded that, when expressed, the genes in this network alter other genes in the breast cancer cells’ extracellular matrix — the scaffolding of proteins and other factors on which cells rest — encouraging a tendency toward metastasis. Although most metastasis research in recent years has revolved around mutations in tumor cells or the nearby tissue environment, Hunter’s laboratory has taken a different approach, searching for germline polymorphisms that could help explain the wide variability in breast cancer metastasis rates. “Initially people focused on the nature of the tumor cell itself and what oncogenes and tumor suppressor genes had been expressed, and then they began to realize that the interaction is between the tumor cell and the host environment,” said Ann Chambers, Ph.D., an oncologist who studies metastasis at the London Health Sciences Centre in Ontario. “Dr. Hunter has now added inherited susceptibility to this, perhaps suggesting new therapeutic approaches.” In the PNAS study, the researchers implanted the Brd4 gene into breast cancer cells in some mice and a “control gene” into breast cancer cells of other mice. They found that mice with the Brd4 gene had fewer metastases than mice with the control gene. The researchers believe that activation of Brd4 (resulting in either an increased amount or function of the protein) reduces tumor growth and metastasis by infl uencing the response of tumor cells to signals from the extracellular matrix. Using human gene information from microarray data from the National Center for Biotechnology Information, Hunter’s team found 379 human genes that are similar to genes affected by Brd4 expression in mice. Differences in the human Brd4 pathway, the researchers say, seemed to drive pathways involving these other genes, ultimately affecting relapse and survival. In fact, starting with the Brd4 gene, the researchers were able to predict survival and relapse in fi ve different groups of breast cancer patients. They could also predict the survival of patients whose breast cancers had not spread to their lymph nodes and/or whose breast cancers were estrogen receptor positive. (About 70% of breast cancers are estrogen receptor positive, which is associated with a lower risk of metastasis.) Another of the group’s reports, published in March in Clinical and Experimental Metastasis, discussed seven candidate metastasis susceptibility genes, including Brd4, Sipa1, and another gene called Rrp1b. All are components of what Hunter and his colleagues call the diasporin pathway, a tumor progression – related transcriptional pathway that predicts breast cancer survival.

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