A Plausible Candidate Turning Off The

RESEARCH HIGHLIGHTS

IN THE NEWS METASTASIS Stress is good for you? Women who experience increased levels of stress A plausible candidate are less likely to develop breast cancer, according to a study by Danish Cancer mortality is most often the suppressor gene Brms1. However, GTPase activating protein (GAP) scientists (Nielsen, N. R. et result of metastasis rather than this gene has no obvious polymor- that negatively regulates RAP1 and al., Br. Med. J. 9 September the primary tumour. Previous phisms that influence metastasis RAP2 GTPases. Human SIPA1 has 2005 (doi: 10.1136/ studies from Kent Hunter’s group and so was discounted from this recently been found to interact bmj.38547.638183.06)). demonstrated that the genetic study. with the water channel aquaporin 2 Stress can reduce oestrogen production and background of the host can influ- To identify other potential can- (AQP2), by its PDZ domain, so the oestrogen is a known risk ence metastatic efficiency. Now, didates the authors used a multiple authors used AQP2 to see if the factor in breast cancer. Hunter and colleagues have identi- cross-mapping strategy that uses alanine to threonine substitution Therefore, the authors fied a candidate gene, Sipa1, with the shared haplotypes in different affected this interaction. They followed the incidence of an amino-acid polymorphism that inbred strains of mice to reduce the found that it did — the FVB allele breast cancer in the 6,689 influences this process. number of candidate genes. This bound AQP2 less effectively. women of the Copenhagen The authors previously used a reduced the number of potential What does this mean biologi- City Heart Study who had assessed their own stress mouse model of breast cancer to genes from 500 to 23, which were cally? Transient transfection assays levels between 1981 and investigate the effect of constitu- then prioritized based on their demonstrated that the FVB allele is 1983. They found that 251 tional genetic polymorphism on known molecular function. After less efficient than the DBA allele at women developed breast metastasis. They expressed the analysing and discounting several reducing the activity of GTP RAP1. cancer, and that those who polyoma middle-T transgene in of the genes, the authors found that AQP2 inhibits this and does so more had put themselves in the various strains of inbred mice and Sipa1 had a polymorphism that effectively with the DBA allele. So, higher stress category were 40% less at risk. through quantitative trait genetic results in an alanine (as found in cells expressing the FVB allele will However, caution has been mapping showed the presence of a the DBA mouse strain) to threonine have reduced levels of Rap–GTP advised from all quarters. putative metastasis efficiency locus (as found in the FVB mouse strain) activity. Reducing the expression “Even though we find a lower (Mtes1) on mouse chromosome 19. substitution in a protein–protein of Sipa1 in cells in vitro indicates risk of breast cancer among This chromosome region, which is interaction domain known as a that SIPA1 modulates the adhesive stressed women, let me orthologous to human 11q12–13, PDZ domain. Sipa1 is a mitogen- properties of cells, consistent with just emphasize that stress cannot be considered a harbours a known metastasis inducible gene that encodes a its effect on RAP1, which is known healthy response”, said lead researcher Naja Rod Nielsen of the National Institute of SIGNALLING The mitogen-activated protein Public Health in Copenhagen kinase (MAPK) signalling pathway (http://www.forbes.com, activates many important cell 9 September 2005). Previously, stress had Turning off the tap processes, such as proliferation, been thought to increase but how are these signals ever the risk of breast cancer. turned off? Madhu Macrae et Emma Pennery from Breast al. report that downstream gene Cancer Care, UK, said targets of the pathway, such as the “We know from talking to gene encoding the ephrin receptor women with breast cancer A2 (EPHA2), mediate a negative that some of them believe feedback loop that is lost in cancer stress to be a contributory cells. factor. This new study is therefore very interesting” In a search for MAPK pathway (http://news.bbc.co.uk, gene targets, Macrae et al. 9 September 2005). observed that expression of the Summing up, Sarah receptor tyrosine kinase EPHA2 Rawlings, of Breakthrough was upregulated fivefold when Breast Cancer, UK, MAPK signalling was activated. reminded people that Interestingly, they also found that “…maintaining a healthy, once EPHA2 is transported to the balanced lifestyle is cell surface, it binds to its ligand, important — we know that ephrin-A1, and MAPK signalling high stress levels can lead to unhealthy behaviour, is downregulated. This seems to which may alter your risk be a negative feedback loop that of breast cancer and other controls MAPK signalling and diseases” (http://www. cell proliferation. guardian.co.uk, Previous studies had shown 9 September 2005). that the EPHA2 receptor tyrosine Patrick Goymer

of Sipa1 decreased the numbers of IN BRIEF pulmonary metastases from a highly metastatic mammary tumour cell line. Conversely, overexpression VACCINES of the FVB allele increased the T cell-mediated suppression of angiogenesis results in numbers of pulmonary metastases. tumor protective immunity. Analysis of human tumours also demonstrated that overexpression of Zhou, H. et al. Blood 106, 2026–2032 (2005) SIPA1 is associated with metastatic Tumour growth can be inhibited by anti-angiogenic progression. intervention. The authors had previously shown that These results demonstrate that vaccination with a complete copy of the murine growth factor Sipa1, as determined by its overall receptor gene Flk1 triggered the production of antibodies protein concentration and/or its against proliferating endothelial cells in the tumour vasculature. availability to inactivate RAP1, Now they show that the use of an engineered minigene modulates metastatic progression. containing only one cytotoxic epitope of Flk1, delivered to The data also predict that homo- mice in a Salmonella-based vector, results in an antibody that zygotes for the DBA allele would prevents angiogenesis and protects against various tumours, but have reduced metastatic capacity does not cross react with healthy tissue. because, in the primary tumour, cells are more likely to closely inter- CANCER GENETICS act with one another. Additional Dido gene expression alterations are implicated in the studies are required to verify this induction of hematological myeloid neoplasms. and to investigate another potential gene close to Sipa1 that might also Fütterer, A. et al. J. Clin. Invest. 115, 2351–2362 (2005) contribute to the Mtes1 locus. Myelodysplastic/myeloproliferative diseases (MDS/MPDs) are a Nicola McCarthy heterogeneous group of myeloid neoplasms that are associated with deletions on chromosome 20q. The authors map the to affect cell–cell interactions. But References and links death inducer-obliterator (DIDO) gene to this location and does Sipa1 influence metastasis? ORIGINAL RESEARCH PAPER Park, Y. G. et al. show that all patients with MDS/MPDs have DIDO-expression Sipa1 is a candidate for the metastasis efficiency A series of experiments in mouse modifier locus Mtes1. Nature Genet. 4 September abnormalities. Furthermore, targeting Dido in mice caused a models showed that RNA inhibition 2005 (doi: 10.1038/ng1635) disease with symptoms similar to those of MDS/MPDs. These results indicate that DIDO might be a tumour suppressor gene for MDS/MPDs. kinase is commonly overexpressed receptor on adjoining cell types TUMORIGENESIS in human cancers, including keeps cell proliferation in check. 40% of breast cancers. So, how When this structure is lost, such Genetic ablation of cyclin D1 abrogates genesis of rhabdoid can cancer cells express high as during tumour formation, tumors resulting from Ini1 loss levels of EPHA2 and maintain EPHA2-expressing cells no Tsikitis, M. et al. Proc. Natl Acad. Sci. USA 102, 12129–12134 (2005) signalling along the MAPK longer interact with ephrin-A1 pathway? A survey of EPHA2 produced by neighbouring cells, Rhabdoid tumours are aggressive paediatric malignancies and its ligand in a panel of 28 resulting in uncontrolled MAPK that arise because of the loss of the tumour suppressor gene breast cancer cell lines revealed signalling and proliferation. INI1. INI1 represses cyclin D1 (CCND1) gene expression, and that cells that overexpress In support of this model, the authors found that Ini1+/–mice develop rhabdoid tumours EPHA2 do not express ephrin- the authors showed that that have defective INI1 expression but express CCND1. A1 — expression of the receptor ERBB transformation, which CCND1 de-repression is therefore important for rhabdoid and its ligand is mutually is mediated by the MAPK tumorigenesis. exclusive. This is because in signalling pathway, is suppressed addition to upregulating the by ephrin-A1 expression in TELOMERES expression of EPH2A, another cultured cells. The authors outcome of MAPK signalling is suggest that maintaining normal XPF nuclease-dependent telomere loss and increased downregulation of the ephrin-A1 interactions between ephrin DNA damage in mice overexpressing TRF2 result in gene EFNA1. ligands and receptors is an premature aging and cancer. The authors propose that in important mechanism of tissue Muñoz, P. et al. Nature Genet. 4 September 2005 (doi: 10.1038/ng1633) normal tissue architecture, one homeostasis that is disrupted cell type downregulates MAPK during the development of breast TRF2, a protein that functions to protect telomeric ends of signalling and is therefore able and other cancers. DNA, paradoxically induces increased rates of skin cancer to express ephrin-A1, whereas Kristine Novak when overexpressed in mouse skin. The authors show that neighbouring cells activate the References and links TRF2 interacts with the ultraviolet light-induced DNA repair MAPK signalling pathway and ORIGINAL RESEARCH PAPER Macrae, M. nuclease XPF and activates XPF function at telomeres. This et al. A conditional feedback loop regulates leads to disruption of the telomere structure and shortening of express only the receptor. This Ras activity through EphA2. Cancer Cell 8, interaction between ligand and 111–118 (2005) the telomeres. In addition, TRF2 is also overexpressed in human tumours, indicating that it can be oncogenic in man.