title: MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1.
abstract: MicroRNAs have key roles in tumor metastasis. Here, we describe the regulation and function of miR-34a and miR-34c (miR-34a/c) in breast cancer metastasis. Expression analysis verified that miR-34a/c expression is significantly decreased in metastatic breast cancer cells and human primary breast tumors with lymph node metastases. Overexpression of miR-34a/c could inhibit breast cancer cell migration and invasion in vitro and distal pulmonary metastasis in vivo. Further studies revealed that Fos-related antigen 1 (Fra-1 or Fosl1) is a downstream target of miR-34a/c as miR-34a/c bound directly to the 3'untranslated region of Fra-1, subsequently reducing both the mRNA and protein levels of Fra-1. Silencing of Fra-1 recapitulated the effects of miR-34a/c overexpression, whereas enforced expression of Fra-1 reverses the suppressive effects of miR-34a/c. Moreover, significant downregulation of miR-34a in metastatic breast cancer tissues was found to be inversely correlated with Fra-1 expression. Our results demonstrate that miR-34a/c functions as a metastasis suppressor to regulate breast cancer migration and invasion through targeting Fra-1 oncogene and suggest a therapeutic application of miR-34 in breast cancer.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Luo
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: F
authors.initials: F
authors.lastname: Ding
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D000099169:Fos-Related Antigen 1
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1; C522425:MIRN34 microRNA, human