Genetic Architecture: How a Cell is Wired
University of Toronto ♦ National Institute of Health ♦ Albert Einstein College of Medicine
Published in Nature Biotechnology, May 15, 2011
A great deal of effort has been invested in elucidating the physical interactions of proteins in order to understand their functional relationships. The research community is also trying to reveal the functional connections between genes. Very few genes that display genetic interaction actually physically interact however, so mapping out the architecture of genetic interactions and how these fit into signaling pathways must be done without using physical association. Researchers in Toronto have used a method known as dosage suppression to plot hundreds of genetic interactions in yeast and plotted these together to create a global genetic interaction network map that can be leveraged to understand how the cell is wired on a high level.
Dosage suppression is a form of genetic interaction that occurs when over-production of one gene compensates for another gene that has been silenced due to mutation. In this study gene expression was bolstered through the ectopic expression of yeast genes. In certain cases, this up-regulation can lead to the rescue of a mutant gene, at which point a genetic interaction or ‘edge’ is established. Researchers collected dosage suppression genetic interactions for 424 essential genes that were annotated in the Saccharomyces Genome Database. These interactions gave rise to a network containing 768 genes with 1,293 genetic interactions. The network was visualized using a program known as Cytoscape in order to place genes with common dosage suppression in distinct clusters. A clustering analysis identified nine clusters, each composed of 30 or more genes corresponding to specific biological processes. Researchers further analyzed the network to illustrate how it can be used to provide mechanistic insight into pathways and complexes, and showed that PKA signaling is linked with kinetochore function.
Dosage suppression is relevant to the development of cancer as gene amplification and gain-of-function mutations are associated with up-regulated gene activity, disease initiation, and progression.
Combination Treatment Cures Breast Cancer in 40% of HER-2+ Transgenic Mice
Saskatchewan Cancer Agency ♦ University of Saskatchewan
Published in Cancer Gene Therapy (npg), May 13, 2011
Human epidermal growth factor receptor (HER-2) is over-expressed in roughly 20% of breast cancer incidents. In some cases of HER-2-positive breast cancer, the humanized anti-HER-2 antibody Trastuzumab (Herceptin) is used for therapy. Unfortunately, most patients that receive the antibody develop resistance to it in time. As a result, the research community has been looking for alternative strategies to target HER-2. Researchers in Saskatchewan have recently released some very impressive results from an animal study wherein mice were treated with an adenovirus-based vaccine.
Adenoviruses can be engineered to express any number of transgenic proteins that elicit potent transgene-product specific CD8+ T-cell responses following injection into the body. In this study researchers constructed a HER-2-expressing adenovirus that was capable of inducing a significant reduction in breast carcinogenesis in transgenic mice. It was noted, however, that the vaccination had to be given prior to tumour formation. Mice that had pre-existing tumours did not benefit from the vaccine. Trastuzumab, while being highly effective at stunting the growth of early-stage tumours, has little to no effect on larger, more mature, tumours. After combining Trastuzumab therapy with the recombinant adenovirus vaccine, researchers realized they had stumbled upon a rather effective treatment. Mice, with well-established tumours, receiving combination therapy did much better than those receiving either monotherapy; 4 out of 10 mice treated were entirely cured of the condition, while there was significant delay in death of the remaining 6 tumour-bearing mice.
These findings suggest that a combinatorial immunotherapy of a HER-2 expressing adenovirus and Trastuzumab could be a new therapeutic approach to the treatment of advanced HER-2 positive breast cancer.