Cancer Res：RANK诱导EMT促进肿瘤转移

RANK蛋白促进人乳腺癌的启动、进展和转移，相关研究论文发表在Cancer Research杂志上，表明抑制这种受体可能对乳腺肿瘤的治疗有效果。

Bellvitge生物医学研究所（IDIBELL）的研究表明，RANK信号转导通路的过度激活通过促进乳腺细胞分化成肿瘤干细胞，使得人类乳腺上皮细胞转移的启动、进展和转移。

RANK信号通路

这项研究是由Bellvitge生物医学研究所（IDIBELL）Eva Gonzalez-Suarez领导。一年前，研究小组发表的一项研究论文证实这条信号途径在小鼠模型中乳腺肿瘤有关。我们看到，当这条途径是过度活跃的时候，动物更容易患上乳腺癌，当药物抑制这条信号途径时肿瘤减少。

这项研究的出发点是观察人身上RANK过度表达的影响。首先研究人员用健康的乳腺上皮细胞株，发现RANK受体的过度表达诱导干细胞和上皮间质转化到成具有恶性肿瘤特征的细胞，但并不发展成肿瘤

下一步是观察蛋白质在乳腺肿瘤细胞的过度表达的影响。我们看到它在肿瘤干细胞中是如何的生成增加的，当我们将RANK注入了动物模型中时，肿瘤发生和转移会增加。

最后，研究人员使用乳腺癌的临床标本。高水平RANK的肿瘤细胞扩散和转移等级也较高。这意味着高水平蛋白质与肿瘤预后不良相关。因此，本研究证实人体细胞中，RANK可能会增加乳腺癌启动、进展及转移。（生物谷：Bioon.com）

doi:10.1158/0008-5472.CAN-12-0044
PMC:
PMID:

RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis

Marta Palafox, Irene Ferrer, Pasquale Pellegrini, Sergi Vila, Sara Hernandez-Ortega, Ander Urruticoechea, Fina Climent, et al.

Paracrine signaling through RANK pathway mediates the expansion of mammary epithelia that occurs during pregnancy and activation of RANK pathway promotes mammary tumorigenesis in mice. In this study we extend these previous data to human cells and demonstrate that the RANK pathway promotes the development of mammary stem cells and breast cancer. Overexpression of RANK (FL-RANK) in a panel of tumoral and normal human mammary cells induces the expression of breast cancer stem and basal/stem cell markers. High levels of RANK in untransformed MCF10A cells induce changes associated with both stemness and transformation including mammary gland reconstitution, epithelial-mesenchymal transition, increased migration and anchorage independent growth. In addition, spheroids of RANK-overexpressing MCF10A cells displayed disrupted acinar formation, impaired growth arrest and polarization, and luminal filling. RANK overexpression in tumor cells with non functional BRCA1, enhances invasiveness in acinar cultures and increases tumorigenesis and metastasis in immunodeficient mice. High levels of RANK were found in human primary breast adenocarcinomas that lack expression of the hormone receptors, estrogen and progesterone, and in tumors with high pathological grade and proliferation index; high RANK/RANKL expression was significantly associated with metastatic tumors. Together, our findings demonstrate that RANK promotes tumor initiation, progression and metastasis in human mammary epithelial cells by increasing the population of CD44+CD24- cells, inducing stemness and epithelial mesenchymal transition. These results suggest that RANK expression in primary breast cancer associates with poor prognosis.