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Keywords | Breast | metastasis | gene expression profi ling |<br />
BRECOSM<br />
Identifi cation of molecular pathways<br />
that regulate the organ-specifi c<br />
metastasis of breast cancer<br />
Summary<br />
The objectives of this project are to identify genes, proteins<br />
and molecular pathways involved in regulating the metastasis<br />
of breast cancer to specifi c organs. To achieve these<br />
objectives we will use a combination of gene expression<br />
profi ling, bioinformatic analysis, histology of human female<br />
breast cancer samples, genetic manipulation of transplantable<br />
tumor cells and transgenic mouse technology. In addition to<br />
fi nding new genes, we aim to analyse to what extent genes<br />
already known to play a role in breast cancer metastasis<br />
specify which organs breast tumors metastasise to. We will<br />
also establish how the currently known genes that are<br />
associated with breast cancer dissemination and the new<br />
ones we identify fi t together into pathways that regulate<br />
organ-specifi c metastasis. These fi ndings will be coupled<br />
with the analysis of clinical trials in which participants in this<br />
consortium are involved. Further deliverables include the<br />
development of improved animal models for the study of<br />
breast cancer metastasis, and the development of diagnostic<br />
methods for determining whether primary tumours already<br />
have metastatic potential. Together, the work packages in<br />
this project will establish a pipeline of activities that unite<br />
basic research into the organspecifi c metastasis of breast<br />
cancer with target validation and clinical application.<br />
Wholemount staining of the epithelial ductal structure in a mouse mammary gland.<br />
The lymph nodes are also visible as densely-stained spheroidal structures.<br />
Problem<br />
Breast cancer is a major health issue and is highly gender relevant.<br />
It is the most often diagnosed female cancer, and the<br />
majority of cases are already invasive at diagnosis. More than<br />
17 % of cancer deaths result from breast tumours, making<br />
breast cancer a major societal problem. Treatment involves<br />
radical and disfi guring surgery, often with long-term side<br />
eff ects such as the development of lymphedema of the arm,<br />
and radiotherapy and chemotherapy, again associated with<br />
severe side eff ects. The eff ects of metastatic spread of<br />
the tumour cells and the formation of secondary deposits in<br />
a wide variety of organs are the cause of death due to breast<br />
cancer. Metastases to organs such as bone and brain are<br />
major causes of suff ering in terminally ill patients.<br />
The incidence of breast cancer increases sharply between<br />
the ages of 30 and 50 meaning that many women in the<br />
prime of life are aff ected by this disease. Not only does this<br />
mean that many families are traumatised, but it also has<br />
severe economic consequences, removing economically<br />
active women from society. Further economic consequences<br />
arise as a result of the high health care costs associated<br />
with treating breast cancer patients.<br />
Clearly improvements in the treatment and management of<br />
breast cancer would have impact on both health and the<br />
economy. By analysing molecular mechanisms that regulate<br />
organ-specifi c metastasis in breast cancer, the BRECOSM<br />
project will identify tools that will contribute to improved<br />
clinical decision-making, prognostic evaluation and therapy<br />
in breast cancer.<br />
BIOLOGY 17<br />
Aims<br />
• To identify genes that are specifi cally up- or downregulated<br />
in breast cancer metastases in specifi c organs.<br />
• To identify gene expression signatures in primary breast<br />
tumours that predict metastasis to specifi c organs or<br />
predict the prognosis of ductal carcinoma in situ (DCIS).<br />
• To determine whether genes already associated with<br />
breast cancer invasiveness and metastasis are expressed<br />
in metastases in all or only a subset of organs.<br />
• To demonstrate whether genes found to be specifi cally<br />
expressed in breast cancer metastases to given organs<br />
play a functional role in organ-specifi c metastasis.<br />
• To elucidate molecular pathways that regulate breast<br />
cancer metastasis to specifi c organs.<br />
• To develop improved animal models for studying organspecifi<br />
c metastasis of breast cancer.<br />
• To produce a prototype microarray chip for diagnostic/<br />
prognostic evaluation.<br />
• To apply the fi ndings on organ-specifi c metastasis in the<br />
clinical setting.
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