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

我们建立了一种新的乳腺癌术后微转移模型，使用MKL-4细胞系，这是一种用成纤维细胞生长因子（FGF）-4和细菌IacZ转染的MCF-7人乳腺癌细胞系。术后给予尿嘧啶和替加氟（UFT）可显著抑制进展。这是第一次证明术后给予5-氟尿嘧啶衍生物对预防乳腺癌微转移进展的有效性。我们还从复发性乳腺癌患者中建立了三种新的人乳腺癌细胞系（KPL-1、KPL-3C和KPL-4）。使用这些细胞系发现了几个有趣的发现。过表达FGF-1或VEGF-B可诱导KPL-1细胞的凋亡非依赖性。我们参与了乳腺癌细胞中FGF家族成员和VEGF家族成员表达的激素调节的研究。几种激素差异调节甲状旁腺相关蛋白（PTHrP）和白细胞介素-6的表达，这两者都是已知的诱导溶骨性骨转移。无论是雌激素或孕酮，醋酸甲羟孕酮（MPA）减少PTHrP的表达，但抗雌激素增加它在KPL-3C细胞。MPA在体内外均能显著降低KIPL-4细胞IL-6的表达。这些转化研究可能有助于了解乳腺癌细胞生物学以及开发新的策略来对抗复发性乳腺癌。

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.