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