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Tumor-Stromal Interactions in Breast Cancer Bone Metastasis
Background: Breast cancer commonly metastasizes to bone and can form osteolytic lesions. A variety of growth factors and cytokines released by cancer cells can promote the activation of osteoclasts, the cells primarily responsible for bone lysis. However, advances in understanding the biology of breast cancer bone metastasis have been limited by the lack of suitable experimental models. Objective/hypothesis: The objective is to characterize a new cell line we have established from a breast cancer bone metastasis, focusing on the expression of cytokines that regulate osteolysis and angiogenesis. We will test the hypothesis that transforming growth factor-beta, which is abundant in bone matrix, regulates the expression of osteolysis-promoting genes in bone metastasis-derived breast cancer cells. Further, we will test the hypothesis that the bone metastasis-derived cells release factors that promote the growth and survival of bone endothelial cells. The specific aims of the proposal are; 1) To characterize the expression patterns of osteolysis-promoting and angiogenic factors by bone metastasis-derived breast cancer cells, and measure changes following treatment with transforming growth factor-beta. 2) Evaluate interactions between bone metastasis-derived breast cancer and bone-derived endothelial cells, measuring the ability of factors expressed by the cancer cells to regulate the motility, growth and survival of endothelial cells. Design and methodology: Expression analyses will be performed using cDNA microarrays, testing samples from breast cancer cells treated with transforming growth factor-beta for altered patterns of expression, focusing on cytokines and growth factors involved in regulating osteolysis and angiogenesis. Validation of differences in expression of genes altered >2.5-fold in the arrays will be done by real-time PCR and/or protein measurements. Cultured murine bone-derived endothelial cells will be used in assays to measure the binding of cancer cells to the endothelial cells, and ability of factors expressed by bone metastasis-derived breast cancer cells to regulate motility, growth and/or survival of the endothelial cells. Potential outcomes and benefits : A better understanding of the biology of breast cancer bone metastasis and the contribution of cancer cell-derived factors will lead to new approaches for the control or prevention of this significant clinical problem.
The purpose of this research is to investigate how breast cancer cells form bone metastases. The likelihood of surviving breast cancer is directly related to whether or not cells have already spread (metastasized) to other places in the body by the time of diagnosis and initial treatment. The most common site for distant metastasis is the bone, where breast cancer cells can cause bone destruction (osteolysis). Bone metastases have serious complications, notably chronic pain and pathological fractures. In normal bone there is a fine balance between bone resorption and new bone growth, mediated by growth factors, cytokines and hormones. The presence of breast cancer cells, which can release many of these growth factors and cytokines, can disrupt bone homeostasis and promote the abnormal activation of osteoclasts, the cells primarily responsible for bone destruction. Progress in understanding the process of bone metastasis has been slow, due in part to the lack of experimental models. Much of the basic research on breast cancer has been performed with a relatively small number of cell lines. However, none of these cell lines were established from bone metastases. We have recently derived a cell line from a bone metastasis of a breast cancer patient, and propose to use these cells to identify factors that promote angiogenesis and local destruction of bone around metastases. The matrix of bone has high concentrations of a multifunctional growth factor, transforming growth factor-beta, which is reported to regulate expression of genes that may be involved in bone metastasis. As part of the characterization of the bone metastasis-derived cell line we will test the hypothesis that transforming growth factor-beta regulates the expression of osteolysis-promoting genes. The bone metastasis-derived breast cancer cells also release factors that promote angiogenesis, the development of blood vessels that are necessary for continued growth of metastases. The interactions between the breast cancer cells and mouse bone endothelial cells will be examined in tissue culture studies, measuring how factors released by the cancer cells promote migration, growth and survival of endothelial cells. Understanding how to regulate, and hence inhibit expression of factors that promote osteolysis or angiogenesis will aid in the design of new strategies to control bone metastasis.