title: Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors.
abstract: The transcription factor RE1 silencing transcription factor (REST) is lost in approximately 20% of breast cancers. Although it is known that these RESTless tumors are highly aggressive and include all tumor subtypes, the underlying tumorigenic mechanisms remain unknown. In this study, we show that loss of REST results in upregulation of LIN28A, a known promoter of tumor development, in breast cancer cell lines and human breast tumors. We found that LIN28A was a direct transcriptional target of REST in cancer cells and that loss of REST resulted in increased LIN28A expression and enhanced tumor growth both in vitro and in vivo, effects that were dependent on heightened LIN28A expression. Tumors lacking REST expression were locally invasive, consistent with the increased lymph node involvement observed in human RESTless tumors. Clinically, human RESTless breast tumors also displayed significantly enhanced LIN28A expression when compared with non-RESTless tumors. Our findings therefore show a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo.
authors.affiliation: Graduate Program in Cellular and Molecular Biology, Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Kearney T W
authors.initials: KT
authors.lastname: Gunsalus
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Wagoner
authors.forename: Kassondra
authors.initials: K
authors.lastname: Meyer
authors.forename: Wyatt B
authors.initials: WB
authors.lastname: Potter
authors.forename: Barry
authors.initials: B
authors.lastname: Schoenike
authors.forename: Soyoung
authors.initials: S
authors.lastname: Kim
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Alexander
authors.forename: Andreas
authors.initials: A
authors.lastname: Friedl
authors.forename: Avtar
authors.initials: A
authors.lastname: Roopra
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C516326:LIN28B protein, human