Journal of the National Cancer Institute Advance Access originally published online on May 27, 2008
JNCI Journal of the National Cancer Institute 2008 100(11):768-769; doi:10.1093/jnci/djn185
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© Oxford University Press 2008.
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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.
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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 cancer 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 influence 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 influencing 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 five 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.
Back to the Mouse
Intrigued by the unexplained variability in breast cancer metastasis rates—that some tumors metastasize while other, seemingly similar, ones do not—Hunter began pursuing inherited metastasis about 10 years ago, beginning with colonies of inbred laboratory mice.
He set up experiments in which males of one inbred strain—the genetically engineered "polyoma middle T" mouse line, all of whom develop breast cancer by 9 weeks of age—were allowed to breed with females from 25–30 other inbred strains. In these new "outbred" strains, which are more genetically analogous to most humans, breast cancer still occurred, but metastasis was greatly altered. Some new strains had a fourfold increase in metastasis, whereas others developed very few. Yet the transgene (the gene that originally was transferred into a strain of mice to create the polyoma middle T strain) was turned on at the same time and to the same level in the new strains and its protein was handled in the same way as in the original inbred polyoma middle T mouse. What was going on?
The most obvious explanation was that although the outbred mice had the same mouse genes as the inbred ones, they had different versions, or polymorphisms, of these genes. Polymorphisms in at least one of these genes greatly affected the cancer's ability to metastasize. Hunter and colleagues then set about mapping regions of the mouse genome that were associated with suppression or enhancement of metastasis.
Eventually, the group found such a gene on mouse chromosome 19. Called Sipa1, the gene had one amino acid substitution that changed the enzymatic function of its protein, resulting in a two- to fourfold reduction in metastasis.
"Just knocking down the function of this protein a little bit had a significant effect on metastasis," Hunter said. "This is completely consistent with the possibility of gene polymorphisms’ having subtle effects on proteins and an enormous effect on breast cancer metastasis."
Relevant to Humans?
The next question was whether the findings in mice would hold true in humans. Hunter's group looked more closely at the Sipa1 gene, trying to determine whether specific single-nucleotide polymorphisms (SNPs) within the human version of the gene were associated with metastasis and other disease characteristics in breast cancer patients.
They collaborated with Hoda Anton-Culver, Ph.D., professor and chair of epidemiology at the University of California, Irvine, School of Medicine, who has maintained a population-based registry of breast cancer patients for more than 10 years. The geneticists looked at DNA samples from 300 randomly selected non-Hispanic white patients in the registry, studying three previously described SNPs from the human Sipa1 gene. These SNPs were not amino acid–substituting polymorphisms like the first SNPs that Hunter had found on the mouse gene; nonetheless, two of them were associated with lymph node involvement and one with estrogen receptor– and progesterone receptor–negative tumors—all characteristics of patient tumors that are likely to metastasize.
As in the mouse, these human genes appeared primarily to regulate proteins in the extracellular matrix. In particular, collagen genes appeared to be involved.
"Now we want to look at other SNPs that we’ve found that are significant in humans and see if the mouse modelers have found something similar in mice," Anton-Culver said. "We need more and bigger integrative studies like this."
A smaller patient cohort from Baltimore—approximately half white and half black—was also studied. The SNPs found in this group were less common than in the California group, suggesting that these particular polymorphisms may be more common in whites.
European Population Studies
Several human studies from Europe have confirmed Hunter's work as well. One group in Sweden and another in Germany have used a population-based Swedish cancer registry to test the possibility that metastasis in breast as well as several other solid tumors is familial.
Kamila Czene, Ph.D., and colleagues in the department of medical epidemiology and biostatistics at the Karolinska Institute in Stockholm studied 2,787 mother–daughter pairs and 831 sister pairs diagnosed with breast cancer from 1961 to 2001. After adjustment for potential confounders, they found that daughters and sisters of women with poor prognoses had a 60% higher 5-year breast cancer mortality rate than daughters and sisters of women who had good prognoses. "Our novel findings suggest that breast cancer prognosis might be inherited," the researchers wrote in their 2007 paper in Breast Cancer Research.
Another breast cancer survival study using the same database was carried out with similar results by Per Lenner, M.D., Ph.D., of the University of Umeå in Sweden and collaborators at the German Cancer Research Center. Studying 1,277 mother–daughter pairs with breast cancer, the investigators found that there was a concordance of prognosis between mothers and daughters. The consistency of the results, noted the investigators, "suggests that the prognosis in breast cancer is in part heritable, which is likely to be explained by yet unknown genetic mechanisms."
The groups also found similar results in prostate, colorectal, bladder, and renal cell cancers.
Many Candidates
A third known metastasis-related gene, Rrp1b, found in both mice and humans, emerged from additional studies by Hunter's group published last year in PLoS Genetics. This gene is thought to be involved in ribosomal RNA processing and interacts in the cell with Sipa1. Rrp1b also seems to be involved in controlling or modulating the expression of extracellular matrix genes, particularly those specifying collagens. "That suggested to us that either the collagen genes are responsible for metastatic susceptibility or are markers of it," Hunter said.
"Because the entire system is so complex, I think there are many other metastasis modifiers," he said. "Fortunately, metastasis is an extremely inefficient process and there are lots of places where you can throw sand into the works. You can subtly alter cell physiology in many different ways that will move you up or down that sliding scale of susceptibility to metastasis. The relative effect of any particular gene might vary dramatically, and some are more important than others."
In the long term, an understanding of inherited susceptibility to metastasis could translate into clinical benefit, Hunter said. "Maybe by better understanding the biology of metastasis, we can identify new treatments or develop preventive agents, or at the very minimum know that we have to monitor these women more frequently so that we can intervene earlier to improve their survival and quality of life."
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