Some solid tumors such as breast cancer have a special predilection to cause osteolytic metastases. The investigators have developed an in vivo model to study the capacity of human breast cancer cells to form osteolytic bone lesions in vivo using a modification of a technique developed by others to study mechanisms of bone metastasis by animal tumors. Human breast cancer cells are inoculated into the left ventricle of the heart of nude mice, and osteolytic bone lesions are then assessed during the following 4 weeks in the vertebrae and extremities by x-ray and quantitative histology. The applicants plan to use this model to characterize the properties of human breast cancer cells which are responsible for bone metastasis and osteolytic bone destruction. In particular, they plan to study specific properties of cultured human breast cancer cells which may be related to metastasis to bone and osteolysis, including expression of cell attachment proteins which bind to laminin, to E-cadherin and the production of proteolytic enzymes or their inhibitors. They also plan to use this model to examine potential therapeutic approaches to prevent or inhibit the development of osteolytic bone lesions. With this model, they will select subpopulations of cells with enhanced capacity to cause osteolytic bone destruction, investigate the role of cell attachment proteins such as laminin and E-cadherin by the use of specific antagonists, antibodies and transfected cells, and the role of matrix metalloproteases and their inhibitors in osteolysis caused by human breast cancer cells in this model. The overall goal is to identify some of these molecular mechanisms which are responsible for osteolysis in vivo, so that rational therapeutic approaches can be devised to prevent or reverse bone destruction associated with metastatic breast cancer.
| Zweemer, R P; Shaw, P A; Verheijen, R M et al. (1999) Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations. J Clin Pathol 52:372-5 |
| Yoneda, T (1998) Cellular and molecular mechanisms of breast and prostate cancer metastasis to bone. Eur J Cancer 34:240-5 |
| Michigami, T; Nomizu, M; Yamada, Y et al. (1998) Growth and dissemination of a newly-established murine B-cell lymphoma cell line is inhibited by multimeric YIGSR peptide. Clin Exp Metastasis 16:645-54 |
| Yoneda, T; Sasaki, A; Dunstan, C et al. (1997) Inhibition of osteolytic bone metastasis of breast cancer by combined treatment with the bisphosphonate ibandronate and tissue inhibitor of the matrix metalloproteinase-2. J Clin Invest 99:2509-17 |
| Mbalaviele, G; Dunstan, C R; Sasaki, A et al. (1996) E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastases in an experimental metastasis model. Cancer Res 56:4063-70 |
