Role of the signal transduction by c-kit receptor tyrosine kinase in the breast

c-kit原癌基因编码受体酪氨酸激酶（KIT）， KIT的配体是干细胞因子（SCF）。KIT在黑色素细胞和正常乳腺上皮中表达，但在黑色素瘤和乳腺癌中表达显著降低。最近有报道称，人转移性黑色素瘤细胞中KIT的强化表达抑制了裸鼠肿瘤的生长和转移，SCF诱导表达KIT的黑色素瘤细胞凋亡。这些结果表明，KIT表达的缺失允许黑色素瘤细胞逃避SCF/KIT介导的凋亡。为了确定SCF/KIT系统对乳腺癌细胞生长和转移的影响，我们将小鼠c-kit基因转染到人KIT阴性转移性乳腺癌细胞系MDA-MB-231中，并随后分析其生长和转移效力。将MDA-MB-231和表达KIT的MDA-MB-231 （MDA-MB-231^<KIT>）细胞在无血清SCF培养基中培养，MDA-MB-231^<KIT>细胞的活细胞数增加，MDA-MB-231细胞的活细胞数增加，而MDA-MB-231细胞的活细胞数增加。此外，[^3H]-胸苷结合实验显示，SCF诱导MDA-MB-231^<KIT>细胞增殖。上述结果表明，SCF/KIT介导的信号可促进MDA-MB-231^<KIT>细胞的体外增殖。裸鼠心脏内注射MDA-MB-231^<KIT>和MDA-MB-231细胞产生骨转移，细胞注射28天后显微镜观察裸鼠骨。MDA-MB-231^<KIT>细胞产生骨转移的数量远大于MDA-MB-231细胞，MDA-MB-231^<KIT>细胞产生骨转移的面积远大于MDA-MB-231细胞。由于骨髓基质细胞大量产生SCF， SCF/KIT介导的信号似乎促进MDA-MB-231^<KIT>细胞在体内的增殖。因此，尽管KIT在黑色素瘤和乳腺癌中的表达相似地降低，但KIT的生物学效应可能在这两种肿瘤中有所不同。少

The c-kit proto-oncogene encodes a receptor tyrosine kinase (KIT), and the ligand for KIT is stem cell factor (SCF). KIT is expressed in melanocytes and normal mammary epithelium, but KIT expression remarkably decreases in melanomas and breast cancers. It has recently been reported that the enforced KIT expression in human metastatic melanoma cells inhibits tumor growth and metastasis in nude mice, and SCF induces apoptosis in the KIT-expressing melanoma cells. These results suggest that the loss of KIT expression allows melanoma cells to escape SCF/KIT-mediated apoptosis. In an effort to determine the effects of SCF/KIT system on growth and metastasis of breast cancer cells, we transfected the murine c-kit gene into the human KIT-negative metastatic breast cancer cell line, MDA-MB-231, and subsequently analyzed its growth and metastatic potency. When MDA-MB-231 and KIT-expressing MDA-MB-231 (MDA-MB-231^<KIT>) cells were cultured in serum-free medium with SCF, the number of viable cell … More s increased in culture of MDA-MB-231^<KIT> cells, but not in culture of MDA-MB-231 cells. Moreover, [^3H]-thymidine incorporation assay showed that SCF induced the proliferation of MDA-MB-231^<KIT> cells. These results indicate that SCF/KIT-mediated signal promotes the proliferation of MDA-MB-231^<KIT> cells in vitro. Bone metastasis was produced by an intracardiac injection of MDA-MB-231^<KIT> and MDA-MB-231 cells into nude mice, and their bones were microscopically examined 28 days after the cell injection. The number of bone metastasis produced by MDA-MB-231^<KIT> cells was much more than that produced by MDA-MB-231 cells, and the area of bone metastasis produced by MDA-MB-231^<KIT> cells was larger than that produced by MDA-MB-231 cells. Since SCF is abundantly produced by bone marrow stromal cells, SCF/KIT-mediated signal seems to promote the proliferation of MDA-MB-231^<KIT> cells in vivo. Thus, although KIT expression similarly decreases in melanomas and breast cancers, it is likely that the biological effects of KIT are different between these two tumors. Less