title: Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2.
abstract: Regulatory pathways that drive early hematogenous dissemination of tumor cells are insufficiently defined. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to define patients with early disseminated breast cancer and identified low retinoic acid-induced 2 (RAI2) expression to be significantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERα, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells.
  
  
  CONCLUSIONS
  We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERα-positive breast tumors. We specified the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer.
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Werner
authors.affiliation: Division of Applied Bioinformatics (G200), German Cancer Research Center (DKFZ), Heidelberg, Germany. National Center for Tumor Diseases (NCT), Heidelberg, Germany. German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Eick
authors.affiliation: Translational Cancer Biology Research Program and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: Elsa
authors.initials: E
authors.lastname: Marques
authors.affiliation: European Molecular Biology Laboratory, Hamburg, Germany.
authors.forename: Vivian
authors.initials: V
authors.lastname: Pogenberg
authors.affiliation: European Molecular Biology Laboratory, Hamburg, Germany.
authors.forename: Annabel
authors.initials: A
authors.lastname: Parret
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. European Laboratory Association, Ibbenbüren, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kemming
authors.affiliation: Cell Signaling Technology, Inc., Danvers, Massachusetts.
authors.forename: Antony W
authors.initials: AW
authors.lastname: Wood
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.affiliation: Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf, Germany. Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Neubauer
authors.affiliation: Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute for Clinical Chemistry, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Riethdorf
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Upasana
authors.initials: U
authors.lastname: Bedi
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Irène
authors.initials: I
authors.lastname: Baccelli
authors.affiliation: Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jücker
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany. Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf, Germany. Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Fehm
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
authors.affiliation: Translational Cancer Biology Research Program and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Klefström
authors.affiliation: European Molecular Biology Laboratory, Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wilmanns
authors.affiliation: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. h.wikman@uke.de.
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000595:Amino Acid Sequence; D001853:Bone Marrow / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D016415:Sequence Alignment; D059467:Transcriptome
chemical_list: D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C118924:RAI2 protein, human; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein