Friend leukemia virus integration 1 activates the Rho GTPase pathway and is associated with metastasis in breast cancer

Abstract

// Wei Song 1 , Wei Li 1 , Lingyu Li 1 , Shilin Zhang 1, 2 , Xu Yan 1 , Xue Wen 1 , Xiaoying Zhang 1 , Huimin Tian 1 , Ailing Li 3 , Ji-Fan Hu 1, 2 , Jiuwei Cui 1 1 Cancer Center, the First Hospital of Jilin University, Changchun, China 2 Stanford University Medical School, VA Palo Alto Health Care System, Palo Alto, CA, USA 3 Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China Correspondence to: Jiuwei Cui, e-mail: cuijiuwei@yahoo.com Jifan Hu, e-mail: jifan@stanford.edu Keywords: FLI1, breast cancer, metastasis, oncogene, RhoA pathway Abbreviations: BC: breast cancer; FLI1: friend leukemia virus integration 1; ROCK: rho-associated coiled coil-containing protein kinase; shRNA: short hairpin RNA; siRNA: small interfering RNA Received: May 01, 2015      Accepted: June 11, 2015      Published: June 24, 2015 ABSTRACT Breast cancer is the most prevalent malignant disease in women worldwide. In patients with breast cancer, metastasis to distant sites directly determines the survival outcome. However, the molecular mechanism underlying metastasis in breast cancer remains to be defined. In this report, we found that Friend leukemia virus integration 1 ( FLI1 ) proto-oncogene was differentially expressed between the aggressive MDA-MB231 and the non-aggressive MCF-7 breast cancer cells. Congruently, immunohistochemical staining of clinical samples revealed that FLI1 was overexpressed in breast cancers as compared with the adjacent tissues. The abundance of FLI1 protein was strongly correlated with the advanced stage, poor differentiation, and lymph node metastasis in breast cancer patients. Knockdown of FLI1 with small interfering RNAs significantly attenuated the potential of migration and invasion in highly metastatic human breast cancer cells. FLI1 oncoprotein activated the Rho GTPase pathway that is known to play a role in tumor metastasis. This study for the first time identifies FLI1 as a clinically and functionally important target gene of metastasis, providing a rationale for developing FLI1 inhibitors in the treatment of breast cancer.