The biology of bone metastasis for breast cancer in expression of growth factor and receptor

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1. Establishment of bone metastasis (BM) for human breast cancer in a nude rat model : To investigate the biology of BM,we have developed an animal model using 8 week aged nude rats with intra-aoric injection of MDA-MB-231 cells (10^6 cells). Four weeks after the injection, all animals (20/20) developed BM,and only one animal with lung metastasis. Using another cell line (MKL-4) transfected b-FGF with enhanced metastatic potential, 20% (1/5) developed BM.Progression of BM was observed by the X-ray examination every week up to 8 weeks after. The growth of tumor may be regulated by the microenvironment in the bone marrow when trapped first. We noticed TGFbeta which is the most abundant factor in bone matrix and released by the bone resorption. Recently, it has been reported the P53 gene regulates the growth of tumor cells related to TGFbeta. In immunohistochemical study, MDA-MB-231 cells in metastatic site overexpressed p53 protein, but MKL-4 did not. TGFbeta was not expressed in both. We have also developed a variant cell line of MDA-MB-231 with highly metastatic potential from spontaneously metastasizing foci of the lung in nude mice. 2. Expression of growth factor and receptor in BM of autopsy specimens : C-met, ER,and c-erbB-2 expressions were observed in 87%, 52%, and 43% of 27 specimens. These results were consistent with primary tumors. Now, we extracted DNA from the paraffin embedded blocks of autopsy specimens for detect of gene amplification. In an animal model, breast cancer cells with different metastatic potentials will be compared by the expression of activated and in-activated TGFbeta with immunohistochemistry, location of the TGFbeta mRNA with in situ hybridization, and p53 point mutation with PCR-SSCP.