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Mechanisms for Controlling Breast Cancer Growth and Skeletal Metastasis

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Annual rept. 15 May 2000-14 May 2001

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Bone morphogenetic protein-2 BMP-2, an osteoblastic growth and differentiation factor is found to inhibit estradiol- stimulated growth of estrogen receptor ER containing MCF7 human breast cancer cells as well as the ER negative but EGF-responsive growth of MDA MB 231 cells. The underlying mechanism for growth inhibition by BMP-2 involved inhibition in retinoblastoma protein pRb phosphorylation, which is essential for the cells to proliferate. We also demonstrated that BMP-2 inhibits mitogen activated protein kinase MAPK activity in these breast cancer cells. Since MAPK is stimulated by most of the cell proliferating mitogens, inhibition of MAPK activity will result in potent inhibition of cell proliferation. Thus BMP-2 is capable of negatively regulating two essential pathways of cell proliferation and could prove to be a good target for drug development in breast cancer cell growth, if it proves to do the same in vivo. In order to test the validity of our in vitro finding we developed a mouse model where we can study the effect of BMP-2 on breast tumor growth. In addition, since bone is the primary site of breast cancer cell metastasis, we developed an assay to quantitate osteolysis in our mouse model caused by breast tumor growth. Using RTPCR we found that breast tumor cells express low or undetectable levels of EMP receptors BMPR . We have overexpressed BMPR and are in the process of overexpressing BMP-2 in breast cancer cells. We will test the transfected cells for growth and metastatic potential in vivo. The results will lay a background for testing BMP-2 as a therapeutic agent for inhibition of breast cancer cell growth and skeletal metastasis.

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  • Medicine and Medical Research

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