Approximately 43,000 women are afflicted with breast cancer every year in Germany. Breast cancer is the predominant type of cancer in women. Almost 10% of breast cancers are known to be due to hereditary alterations of the germ line. Dr Kay-Uwe Wagner, a research grant holder of the Deutsche Forschungsgemeinschaft (DFG), is a member of a group of scientists led by Chu-Xia Deng and Lothar Hennighausen at the National Institutes of Health (NIH). By using an animal model this group has now elucidated the mechanism underlying hereditary breast cancer. The results of their studies with genetically modified mice will be reported in the May issue the scientific journal Nature Genetics.
It has been known for some time that mutations within the BRCA-1 gene play an essential role in the generation of breast cancer and a variety of other cancer types. In its normal state this gene carries out important functions within the cell. What was not known so far was an explanation for the occurrence of tumours when the gene ceases to function.
In extensive studies carried out over a period of three years Deng's group tried to find out how tumours evolve. Kay-Uwe Wagner and his colleagues generated mice harbouring a mutated non-functional BRCA-1 gene in the mammary gland cells while the gene remained functional in all other body cells. This was achieved by making use of special genes that can be utilised like 'molecular scissors' recognising and cleaving segments of the mouse genome. Rodents treated in this way are known as 'knock-out' mice because a specific gene has been inactivated (knocked-out) specifically.
One fifth of the mice that had their BRCA-1 gene removed from the mammary gland cells developed a tumour within one year. The scientists noted that another gene, the p53 gene, had also become altered in these tumours. The p53 gene has been known for some time to be involved also in the generation of cancers. Thus the researchers generated 'double knock-out' mice specifically carrying mutated BRCA-1 and p53 genes in their mammary gland cells. With 8 out of 11 mice the majority of the double mutant mice suffered from breast cancers and tumours grew twice as fast.
With their experiments the researchers were able for the first time to prove what had been suspected for quite some time, namely that the BRCA-1 gene acts as a tumour suppressor since it is involved in repairing damaged genetic material. Its loss of function causes a genetic instability that favours the manifestation of further mutations. Under normal conditions a variety of 'guardian' genes, including p53, come into play. They force the cell to die before a tumour can develop. However, if the p53 gene is also mutated this protective mechanisms is overruled and allows the tumour to grow.
The animal model developed by the NIH researchers can be employed now to develop drugs capable of influencing tumor formation or even suppressing it. Furthermore, this model could be instrumental in analysing the role of environmental factors such as UV light or ionising radiation in tumorigenesis.
Dr. Uwe-Kay Wagner is a former student of agricultural science of the University of Leipzig and received his Ph.D. from the University of Halle. Presently he is at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland.