Establishment of a postsurgical micro-metastasis model of breast cancer and development of new postsurgical adjuvant therapies

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We have established a new postsurgical micrometastasis model of breast cancer using the MKL-4 cell line, which is a transfectant of MCF-7 human breast cancer cell line with fibroblast growth factor (FGF)-4 and bacterial IacZ.Removal of transplanted umors from nude mice at the time of occurrence of micrometastasis significantly enhanced the progression of micrometastasis in either lymph nodes or distant organs. Postsurgical administration of uracil and tegafur (UFT) significantly inhibited the progression. This is the first demonstration of the effectiveness of postsurgical administration of a 5-fluorouracil derivative for preventing the progression of micrometastasis of breast cancer.We have also established three new human breast cancer cell lines (KPL-1, KPL-3C and KPL-4) from patients with recurrent breast cancer. Several interesting findings have been found using these cell lines. Overexpression of FGF-l or vascular endothelial growth factor (VEGF)-B may induce hormone-independence of the KPL-1 cells. We have been involved in the study of hormonal ceguJation of the expression of FGF family members and VEGF family members in breast cancer cells. Several hormones differentially regulate the expression of parathyroid hormone-related protein (PTHrP) and interleukin-6, both of which are known to induce osteolytic bone metastasis. Either estrogen or a progestin, medroxyprogesterone acetate (MPA) decreased PTHrP expression but antiestrogens increased it in KPL-3C cells. MPA significantly decreased IL-6 expression of KIPL-4 cells both in vitro and in vivo. These translational research may contribute to understanding of breast cancer cell biology as well as to the development of new strategies against recurrent breast cancer.