Community Research and Development Information Service - CORDIS

FP6

BRECOSM Report Summary

Project ID: 503224
Funded under: FP6-LIFESCIHEALTH
Country: Germany

Final Report Summary - BRECOSM (Identification of molecular pathways that regulate the organ-specific metastasis of breast cancer)

The objectives of the BRECOSM project were to identify genes, proteins and molecular pathways involved in regulating the metastasis of breast cancer to specific organs. To achieve these objectives we used a combination of gene expression profiling, bioinformatic analysis, histology of human breast cancer samples, genetic manipulation of transplantable tumour cells and transgenic mouse technology. In addition to finding new genes and gene expression profiles, we have analysed to what extent genes already known to play a role in breast cancer metastasis specify which organs breast tumours metastasise to. We have also established how some of the currently known genes that are associated with breast cancer dissemination and the new ones we have identified fit together into pathways that regulate organ-specific metastasis.

These findings have been coupled with the analysis of clinical trials that participants in this consortium are involved in. Further deliverables included the development of improved animal models for the study of breast cancer metastasis, and the development of diagnostic methods for determining whether primary tumours already have metastatic potential. Importantly, all deliverables have been achieved.

During the BRECOSM project many novel breast cancer cell lines have been established, for example with loss or gain of function of genes thought to play a role in organ-specific metastasis of breast cancer. Many of these approaches have used inducible modulation of gene expression. These novel cell lines have been used either for in vitro studies, or have been implanted into experimental animals to assess the effect of modified gene expression on patterns of metastasis. These approaches have yielded many important end results. Several genes have thereby been identified that regulate the metastasis of organ-specific metastasis of breast cancer to the lymph nodes, lungs and bone. Moreover, signal transduction pathways and other molecular regulatory mechanisms have been pieced together that regulate breast cancer metastasis, and novel mechanisms of breast cancer invasive behaviour have been uncovered. Interestingly, most of these genes and regulatory pathways are relevant for metastasis to multiple organs rather than just to a single site, probably reflecting the promiscuous dissemination pattern of breast cancer. The demonstration of the relevance of these findings for human tumours has focused on the use of tissue microarrays to allow the simultaneous assessment of protein expression in large cohorts of human breast cancers and their metastases.

Much effort in the BRECOSM project has focused on the establishment of transgenic and knockout mice that have loss or gain of function of genes thought to be involved in the organ-specific metastasis of breast cancer, and the breeding of the mice with other lines that develop breast cancer spontaneously. In addition, new methods for the analysis of these mice have been developed. The outcome of these activities is the accruement of many novel models for studying breast cancer metastasis whose analysis has already demonstrated the function of candidate genes in breast cancer metastasis to particular organs. This resource will continue to provide important insights into breast cancer metastasis for many years to come.

In addition to making major advances in our basic understanding of breast cancer metastasis, several participants have been using the knowledge generated in a translational way to develop new methods for treating breast cancer. Inhibitors for several proteins shown by BRECOSM partners to regulate breast cancer metastasis have been developed, including small molecular weight chemicals and antibody toxins. Furthermore, some of these inhibitors have been tested in clinical trials. Continued exploitation of the BRECOSM results in this way over the next few years holds the promise of having significant impact in the clinical management of breast cancer.

However, it is also necessary to point out that despite this success, more could have been achieved in the parts of the project that aimed at target identification through the analysis of clinical material using microarray chip technologies. A major problem we encountered was the quality and availability of clinical samples. Banks of samples that were originally to be used were found to be either of poor quality or were not made available. These issues are particularly pertinent to projects like BRECOSM in which access to clinical samples of metastases is critical: several of our findings did not reach statistical significance due to limited sample numbers. This issue is compounded by the problem that only very limited numbers of samples are available Europe-wide (and indeed world-wide) due to the fact that metastases are often not removed surgically. On the basis of our experience, we would recommend that this issue is something that needs to be tackled at the EU level. For example, EU-wide standard operating procedures could be established that ensure the banking of good quality samples. Another useful activity would be the coordination of virtual EU-wide banks of clinical samples that can be accessed on a collaborative basis by researchers wishing to answer fundamental questions for which only limited samples are available.

The BRECOSM project will impact on the breast cancer research sector in several ways. The many important publications arising from the BRECOSM project will inform further research worldwide and will form the basis on which many other researchers can base their future work. The BRECOSM project has also generated a wide variety of resources, ranging from gene expression profiles, plasmids, antibodies, cell lines and genetically modified animals. Once intellectual property is protected (if appropriate) and the results are published, these resources will be made available to the broader scientific community, acting as a valuable support and impetus for further studies by many different laboratories.

Furthermore, many young scientists have been trained by BRECOSM participants during the project. This mentoring leaves a legacy for future research as these young scientists progress through their careers, either in academic science or in the industrial setting. In particular, it is important to point out that BRECOSM has already had an impact on the research careers of several female scientists as the result of the 'Women in science' mentoring seminar that BRECOSM organised.

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UNIVERSITY OF HEIDELBERG
TRIDOMUS-Gebäude Haus C, Ludolf-Krehl-Str. 13 - 17
D-68167 MANNHEIM
Germany
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