title: IMP3 promotes stem-like properties in triple-negative breast cancer by regulating SLUG.
abstract: IMP3 (insulin-like growth factor-2 mRNA binding protein 3) is an oncofetal protein whose expression is prognostic for poor outcome in several cancers. Although IMP3 is expressed preferentially in triple-negative breast cancer (TNBC), its function is poorly understood. We observed that IMP3 expression is significantly higher in tumor initiating than in non-tumor initiating breast cancer cells and we demonstrate that IMP3 contributes to self-renewal and tumor initiation, properties associated with cancer stem cells (CSCs). The mechanism by which IMP3 contributes to this phenotype involves its ability to induce the stem cell factor SOX2. IMP3 does not interact with SOX2 mRNA significantly or regulate SOX2 expression directly. We discovered that IMP3 binds avidly to SNAI2 (SLUG) mRNA and regulates its expression by binding to the 5' UTR. This finding is significant because SLUG has been implicated in breast CSCs and TNBC. Moreover, we show that SOX2 is a transcriptional target of SLUG. These data establish a novel mechanism of breast tumor initiation involving IMP3 and they provide a rationale for its association with aggressive disease and poor outcome.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Samanta
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Goel
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Pursell
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chang
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Khan
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lim
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Mercurio
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014411:Neoplastic Stem Cells; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C498780:IGF2BP3 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors