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    Research Grants Awarded

    Genetics of Brain Metastasis in Breast Cancer

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    A particularly devastating site of breast cancer spread is the brain. While approximately one-third of breast cancer patients are affected, very little is known about how tumor cells invade and grow in the brain and consequently there is little that can be done to prevent or reverse the spread of breast cancer to this organ. The limiting factor in acquiring information needed to devise effective therapies has been the availability of suitable models for studying brain metastasis. Recently, our laboratory have developed a powerful syngeneic mouse model for studying the spread of breast tumor cells from the mammary gland to the brain and other organs affected in breast cancer. The proposed project will make use of the model to identify genes that are involved in brain metastasis. The model is based on the well-characterized 4T1 cell line, a metastatic mouse mammary tumor cell line that we have shown metastasizes to brain when introduced orthotopically. The line has been modified with a luciferase reporter gene and drug resistance genes to facilitate analysis of in vivo metastasis and isolation of metastasized cells from organ tissues. A FLP recombinase site has been introduced into the line to allow targeted integration of genes for over-expression experiments and stably-expressed RNAi constructs for gene silencing experiments. Variants of the engineered line with increased propensity to colonize brain will be isolated from brain metastases after repeated cycles of in vivo metastasis. Gene expression analysis using microarrays will be used to identify genes that are potentially involved. Over-expression and gene silencing experiments will then be used to verify the involvement of putative brain metastasis genes in processes related brain metastasis. The project is expected to result in identification of several genes that will serve as new targets for breast cancer therapy. Knockdown and over-expressing cell lines produced from these studies will serve as valuable tools in future experiments for investigating the function of identified genes in processes related to brain metastasis and the model itself will provide an effective means of testing drugs for therapeutic effects on breast tumor metastasis to brain and other organs.

    Lay Abstract:
    While breast cancer initially develops in the breast, it is the spread of tumor cells to other organs that is responsible for the disease. A particularly devastating site of breast cancer spread is the brain. While approximately one-third of breast cancer patients are affected, little is known about how tumor cells invade and grow in the brain and consequently there is little that can be done to prevent or reverse the spread to this organ. The limiting factor needed to devise effective therapies to counteract brain metastasis is the availability of suitable models for studying the process. Our laboratory has recently developed a mouse model, based on the metastatic mammary tumor cell line 4T1, for studying the spread of breast tumor cells from the mammary gland to all organs affected in breast cancer including brain. The proposed project will use the model to identify genes that are involved in brain metastasis. Biophotonic imaging, a recently developed imaging technique that allows visualization of light emitting cells in live animals, will be used to follow growth and metastasis of genetically engineered 4T1 cells following implantation in the mouse mammary gland. The genome of these cells has been engineered by incorporation of a light-emitting firefly luciferase gene, drug resistance genes, and a specialized site into which DNA can be inserted for gene silencing experiments. The engineered cells will be introduced in mice and those that spread to brain will be isolated and cloned. These cells will have incorporated genetic changes that facilitate metastatic spread to the brain. Expression of genes in these cells will be compared to the original 4T1 cells using microarray analysis, a genomic technique that allows the investigator to determine the expression of thousands of gene simultaneously. The analysis will reveal differences in gene expression that are likely to be involved in brain metastasis. The involvement of specific genes in brain metastasis will then be demonstrated by inhibiting their expression in the tumor cells and studying the effect of the modification on metastasis. The newly established cell lines will provide valuable tools for further analyzing the roles of identified brain metastasis genes in breast cancer progression. The project will produce new target genes for diagnosis, prognosis and treatment of breast cancer and a novel model for studying metastasis to brain and other organs affected in the disease.