title: miR-221/222 targeting of trichorhinophalangeal 1 (TRPS1) promotes epithelial-to-mesenchymal transition in breast cancer.
abstract: Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expression of epithelial-specific genes and increase expression of mesenchymal-specific genes. In addition, expression of these miRNAs increased cell migration and invasion, which collectively are characteristics of the epithelial-to-mesenchymal transition (EMT). The basal-like transcription factor FOSL1 (also known as Fra-1) directly stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. The miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting of the 3' untranslated region (3'UTR) of TRPS1 (trichorhinophalangeal syndrome type 1), which is a member of the GATA family of transcriptional repressors. TRPS1 inhibited EMT by directly repressing expression of ZEB2 (Zinc finger E-box-binding homeobox 2). Therefore, miR-221/222 may contribute to the aggressive clinical behavior of basal-like breast cancers.
authors.affiliation: Department of Molecular Diagnostics and Cancer Cell Biology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Stinson
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
authors.forename: Alex T
authors.initials: AT
authors.lastname: Adai
authors.forename: Nancy
authors.initials: N
authors.lastname: Yu
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Carol
authors.initials: C
authors.lastname: O'Brien
authors.forename: Jill
authors.initials: J
authors.lastname: Spoerke
authors.forename: Suchit
authors.initials: S
authors.lastname: Jhunjhunwala
authors.forename: Zachary
authors.initials: Z
authors.lastname: Boyd
authors.forename: Thomas
authors.initials: T
authors.lastname: Januario
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Newman
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Søren
authors.initials: S
authors.lastname: Warming
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Lukas
authors.initials: L
authors.lastname: Amler
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Yeh
authors.forename: David
authors.initials: D
authors.lastname: Dornan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099169:Fos-Related Antigen 1
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D020930:MAP Kinase Kinase Kinases; D035683:MicroRNAs; D009363:Neoplasm Proteins; D016760:Proto-Oncogene Proteins c-fos; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D014157:Transcription Factors; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099169:Fos-Related Antigen 1; C525709:MIR221, human; C525710:MIR222, human; C108387:TRPS1 protein, human; C492363:ZEB2 protein, human