ROR1在SRC-1引起的乳腺癌恶性转移中的作用机制

The high mortality rate of breast cancer is largely attributed to metastasis and invasion. We have previous found that SRC-1 specifically promoted mammary tumor cell metastasis to the Lung. ROR1 also funtioned in cellular EMT and metastasis and its levels were increased in cancer stem cells. Combining the ChIP-sequence and expression array datasets, we identified ROR1 as a target gene of SRC-1, and it was significant downregulation following SRC-1 knowdown. Taken together, we hypotheze ROR1 is involved in breast cancer metastasis mediated by SRC-1. We aimed at investigating the function of ROR1 in breast cancer metastasis mediated by SRC-1 through knowdown ROR1 in the SRC-1 overexpressing cells, and elaborate the mechanism of SRC-1 upregulating ROR1 and search for new transcription factors. We will also investigate the function of ROR1 in activation of breast cancer stem cells by overexpressing ROR1 in normal mammary epithelial cells and tumor cells. Utilizing the clinical materials, we will analyze the expression and relationship between ROR1 and SRC-1 as well as the genes involved in stem cells, and evaluate its clinical significance. Thus, our research will provide theory basis for mechanism of breast cancer metastasis and potential therapeutic targets.

肿瘤细胞的转移和侵袭是引起乳腺癌患者死亡的重要原因。本课题组前期研究证明SRC-1能促进乳腺癌细胞的恶性转移。最近研究发现，ROR1也可促进乳腺癌细胞的EMT和恶性转移，且在肿瘤干细胞中表达水平升高。ChIP-sequence和芯片结果表明SRC-1可上调ROR1基因表达，且将SRC-1敲低后可导致ROR1表达水平下降。因此ROR1可能在SRC-1引起的乳腺癌细胞恶性转移中起到重要作用。本项目拟通过在乳腺癌细胞中过表达SRC-1的同时敲低ROR1，研究其对SRC-1介导的乳腺癌细胞恶性转移的影响；分析SRC-1上调ROR1表达的分子机制，并寻找新的ROR1调节因子；探讨ROR1在乳腺癌干细胞激活中的作用；结合临床资料，分析乳腺癌患者组织中ROR1与SRC-1及干性基因表达的相关性，并评估其临床意义。本项目成果将为乳腺癌恶性转移的分子机制提供新的理论基础，为药物开发提供新的思路。