MECHANISMS BY WHICH METASTASIZING OSTEOLYTIC BREAST CANCER INTERACTS WITH BONE

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Breast cancer has a special predilection to cause osteolytic metastases. This is a much more common problem than that of hypercalcemia, and is responsible for considerable morbidity and mortality in patients with many common solid tumors. We have recently modified an in vivo model of bone metastasis to allow us to study the mechanisms involved in osteolysis mediated by human breast cancer cells, and human breast cancer cell metastasis to bone. We plan to use this model to characterize the interactions which occur between metastasizing human breast cancer cells and the bone microenvironment. Our hypothesis is that normal bone remodeling releases factors into the bone microenvironment which stimulate aggressive growth and behavior of human breast cancer cells in this site, and that by altering rates of remodeling by pharmacologic inhibitors of bone resorption, we can limit tumor growth in bone. Our approach is to use this in vivo model and alter rates of bone remodeling in tumor bearing nude mice. Nude mice will be inoculated with MDA-231 human breast cancer cells and subsequent osteolysis in the vertebrae and extremities will be assessed by x-ray and quantitative bone histomorphometry. In the first series of experiments, we will use inhibitors of bone resorption such as the bisphosphonates and assess the effects of inhibition of bone remodeling on tumor growth in bone and the development of osteolytic metastases. In the second series of experiments we will examine the development of metastases in tumor bearing mice which have been exposed to stimulators of bone resorption and bone remodeling such as IL-I and PTH-rP. In a third series of experiments, we will use in vitro techniques to examine specific factors in the bone microenvironment which may be responsible for enhancing breast cancer cell growth in bone. Our hope is that such studies will not only allow us to develop better understanding of the responsible mechanisms, but also more appropriate therapies to prevent the formation of osteolytic lesions and to treat established osteolytic lesions, and hopefully to eventually reverse the dismal picture this common complication of cancer currently exhibits.