title: Genetic and pharmacologic inhibition of eIF4E reduces breast cancer cell migration, invasion, and metastasis.
abstract: The translation initiation factor eIF4E is an oncogene that is commonly overexpressed in primary breast cancers and metastases. In this article, we report that a pharmacologic inhibitor of eIF4E function, ribavirin, safely and potently suppresses breast tumor formation. Ribavirin administration blocked the growth of primary breast tumors in several murine models and reduced the development of lung metastases in an invasive model. Mechanistically, eIF4E silencing or blockade reduced the invasiveness and metastatic capability of breast cancer cells in a manner associated with decreased activity of matrix metalloproteinase (MMP)-3 and MMP-9. Furthermore, eIF4E silencing or ribavirin treatment suppressed features of epithelial-to-mesenchymal transition, a process crucial for metastasis. Our findings offer a preclinical rationale to explore broadening the clinical evaluation of ribavirin, currently being tested in patients with eIF4E-overexpressing leukemia, as a strategy to treat solid tumors such as metastatic breast cancer.
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Filippa
authors.initials: F
authors.lastname: Pettersson
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Sonia V
authors.initials: SV
authors.lastname: Del Rincon
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Emond
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Huor
authors.affiliation: Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Elaine
authors.initials: E
authors.lastname: Ngan
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ng
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Monica C
authors.initials: MC
authors.lastname: Dobocan
authors.affiliation: Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. wmiller@ldi.jgh.mcgill.ca.
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D012254:Ribavirin / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D016212:Transforming Growth Factor beta; D012254:Ribavirin; D020780:Matrix Metalloproteinase 9