Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1

// Xiayang Xie 1, 2 , Shou-Ching Tang 3, 4 , Yafei Cai 3 , Wenhu Pi 3 , Libin Deng 3 , Guangyu Wu 5 , Alain Chavanieu 6 , Yong Teng 1, 3, 7 1 Department of Oral Biology, Augusta University, Augusta, GA, USA 2 Department of Pediatrics, Emory Children’s Center, Emory University, Atlanta, GA, USA 3 Georgia Cancer Center, Augusta University, Augusta, GA, USA 4 Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China 5 Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA 6 Institut des Biomolecules Max Mousseron (IBMM), UMR 5247, Universite de Montpellier, CNRS, ENSCM, France 7 Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA Correspondence to: Yong Teng, email: yteng@augusta.edu Keywords: ARF1, breast cancer, metastasis, LM11, zebrafish Received: June 14, 2016      Accepted: August 05, 2016      Published: August 10, 2016 ABSTRACT Metastasis is the major cause of cancer-related death in breast cancer patients, which is controlled by specific sets of genes. Targeting these genes may provide a means to delay cancer progression and allow local treatment to be more effective. We report for the first time that ADP-ribosylation factor 1 ( ARF1 ) is the most amplified gene in ARF gene family in breast cancer, and high-level amplification of ARF1 is associated with increased mRNA expression and poor outcomes of patients with breast cancer. Knockdown of ARF1 leads to significant suppression of migration and invasion in breast cancer cells. Using the orthotopic xenograft model in NSG mice, we demonstrate that loss of ARF1 expression in breast cancer cells inhibits pulmonary metastasis. The zebrafish-metastasis model confirms that the ARF1 gene depletion suppresses breast cancer cells to metastatic disseminate throughout fish body, indicating that ARF1 is a very compelling target to limit metastasis. ARF1 function largely dependents on its activation and LM11, a cell-active inhibitor that specifically inhibits ARF1 activation through targeting the ARF1-GDP/ARNO complex at the Golgi, significantly impairs metastatic capability of breast cancer cell in zebrafish. These findings underline the importance of ARF1 in promoting metastasis and suggest that LM11 that inhibits ARF1 activation may represent a potential therapeutic approach to prevent or treat breast cancer metastasis.