Elliott Bruce E, Hung Wesley L, Boag Alexander H, Tuck Alan B
Cancer Research Laboratories, Department of Pathology, Queen's University, Kingston, Canada.
Can J Physiol Pharmacol. 2002 Feb;80(2):91-102. doi: 10.1139/y02-010.
North American women have a one in eight lifetime risk of developing breast cancer, and approximately one in three women with breast cancer will die of metastases. We, and others, have recently shown that high levels of expression of hepatocyte growth factor (HGF) and its receptor Met are associated with invasive human breast cancer and may be causally linked to metastasis. This high level of HGF and Met expression has been considered as a possible indicator of earlier recurrence and shortened survival in breast cancer patients. In contrast, HGF expression (but not Met) is strongly suppressed in normal breast epithelial cells. HGF and Met are therefore candidate targets for therapeutic intervention in the treatment of breast cancer. We have recently demonstrated that sustained activation or hyper-activation of c-Src and Stat3, which occurs in invasive breast cancer, can stimulate strong expression of HGF in carcinoma cells. In contrast, transient induction of Stat3 occurs in normal epithelium and promotes mammary tubulogenesis. We hypothesize that increased autocrine HGF-Met signaling is a critical downstream function of c-Src-Stat3 activation in mammary tumorigenesis. Future studies will identify novel Stat3 consensus sites that regulate HGF promoter activity and HGF expression preferentially in carcinoma cells and could lead to novel therapeutic drugs that specifically block HGF expression in mammary carcinoma cells, and which could be used in combined treatments to abrogate metastasis.
北美女性一生中患乳腺癌的风险为八分之一，且约三分之一的乳腺癌女性会死于转移。我们及其他研究人员最近表明，肝细胞生长因子（HGF）及其受体Met的高表达与侵袭性人类乳腺癌相关，且可能与转移存在因果联系。HGF和Met的这种高表达被认为可能是乳腺癌患者早期复发和生存期缩短的一个指标。相比之下，正常乳腺上皮细胞中HGF的表达（而非Met）受到强烈抑制。因此，HGF和Met是乳腺癌治疗中治疗干预的候选靶点。我们最近证明，侵袭性乳腺癌中发生的c-Src和Stat3的持续激活或过度激活可刺激癌细胞中HGF的强烈表达。相比之下，Stat3在正常上皮细胞中发生短暂诱导并促进乳腺小管形成。我们推测，自分泌HGF-Met信号的增加是乳腺肿瘤发生过程中c-Src-Stat3激活的关键下游功能。未来的研究将确定新的Stat3共有序列位点，这些位点优先调节癌细胞中HGF启动子活性和HGF表达，并可能导致新型治疗药物，特异性阻断乳腺癌细胞中HGF的表达，并可用于联合治疗以消除转移。
