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在黑素细胞和正常乳腺上皮中表达，但在黑色素瘤和乳腺癌中的表达显著减少。最近有报道称，KIT在人转移性黑色素瘤细胞中的增强表达抑制了裸鼠肿瘤的生长和转移，而SCF则诱导表达KIT的黑色素瘤细胞发生凋亡。这些结果表明，KIT表达的缺失使黑色素瘤细胞能够逃脱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基因导入人KIT阴性的转移性乳腺癌细胞系MDA-MB-231，并对其生长和转移潜能进行了分析。将mda-MB-231和表达Kit的mda-MB-231细胞在有干细胞因子的无血清培养液中培养时，活细胞数…培养的MDAMB-231细胞的S数增加更多，而MDAMB-231细胞的培养数增加不明显。此外，[~3H]-胸腺嘧啶核苷掺入实验表明，SCF可诱导MDA-MB-231细胞增殖。这些结果表明，SCF/KIT介导的信号可促进体外培养的MDA-MB-231和KIT&GT；细胞的增殖。将MDA-MB-231细胞和MDA-MB-231细胞注入裸鼠体内，造成骨转移模型，28d后取骨组织进行光镜检查。MDA-MB-231细胞产生的骨转移数目明显多于MDA-MB-231细胞，且骨转移面积大于MDA-MB-231细胞。由于SCF由骨髓基质细胞大量产生，SCF/KIT介导的信号似乎促进了体内MDA-MB-231和KIT&GT；细胞的增殖。因此，尽管KIT在黑色素瘤和乳腺癌中的表达类似地降低，但KIT的生物学效应在这两种肿瘤中可能是不同的。较少

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