title: ADP-ribosylation factor 1 expression regulates epithelial-mesenchymal transition and predicts poor clinical outcome in triple-negative breast cancer.
abstract: Metastatic capacities are fundamental features of tumor malignancy. ADP-ribosylation factor (ARF) 1 has emerged as a key regulator of invasion in breast cancer cells. However, the importance of this GTPase, in vivo, remains to be demonstrated. We report that ARF1 is highly expressed in breast tumors of the most aggressive and advanced subtypes. Furthermore, we show that lowered expression of ARF1 impairs growth of primary tumors and inhibits lung metastasis in a murine xenograft model. To understand how ARF1 contributes to invasiveness, we used a poorly invasive breast cancer cell line, MCF7 (ER+), and examined the effects of overexpressing ARF1 to levels similar to that found in invasive cell lines. We demonstrate that ARF1 overexpression leads to the epithelial-mesenchymal transition (EMT). Mechanistically, ARF1 controls cell-cell adhesion through ß-catenin and E-cadherin, oncogenic Ras activation and expression of EMT inducers. We further show that ARF1 overexpression enhances invasion, proliferation and resistance to a chemotherapeutic agent. In vivo, ARF1 overexpressing MCF7 cells are able to form more metastases to the lung. Overall, our findings demonstrate that ARF1 is a molecular switch for cancer progression and thus suggest that limiting the expression/activation of this GTPase could help improve outcome for breast cancer patients.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schlienger
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Shirley
authors.initials: S
authors.lastname: Campbell
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pasquin
authors.affiliation: Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Gaboury
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montreal, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Claing
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000096:biosynthesis*; D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D020823:ADP-Ribosylation Factor 1
keywords: ADP-ribosylation factor (ARF); EMT; breast cancer; invasion; metastasis