title: Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1.
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.
authors: Department of Oral Biology, Augusta University, Augusta, GA, USA.|Department of Pediatrics, Emory Children's Center, Emory University, Atlanta, GA, USA.
authors: Xiayang
authors: X
authors: Xie
authors: Georgia Cancer Center, Augusta University, Augusta, GA, USA.|Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China.
authors: Shou-Ching
authors: SC
authors: Tang
authors: Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors: Yafei
authors: Y
authors: Cai
authors: Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors: Wenhu
authors: W
authors: Pi
authors: Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors: Libin
authors: L
authors: Deng
authors: Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA.
authors: Guangyu
authors: G
authors: Wu
authors: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM, France.
authors: Alain
authors: A
authors: Chavanieu
authors: Department of Oral Biology, Augusta University, Augusta, GA, USA.|Georgia Cancer Center, Augusta University, Augusta, GA, USA.|Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA.
authors: Yong
authors: Y
authors: Teng
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D030801:Animals, Genetically Modified; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006056:Golgi Apparatus / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000473:pathology* / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000235:genetics
chemical_list: D000814:Aniline Compounds; D001562:Benzimidazoles; D020690:GTPase-Activating Proteins; C521938:LM11 compound; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C102474:cytohesin-2; D006153:Guanosine Diphosphate; D020823:ADP-Ribosylation Factor 1
keywords: ARF1; LM11; breast cancer; metastasis; zebrafish