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Cancer Discov. 2015 May;5(5):506-19. doi: 10.1158/2159-8290.CD-14-1042. Epub 2015 Feb 25.

Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2.

Author information

1
Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2
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.
3
Translational Cancer Biology Research Program and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
4
European Molecular Biology Laboratory, Hamburg, Germany.
5
Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. European Laboratory Association, Ibbenbüren, Germany.
6
Cell Signaling Technology, Inc., Danvers, Massachusetts.
7
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
8
Department of Obstetrics and Gynecology, University of Duesseldorf, Duesseldorf, Germany. Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, Germany.
9
Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute for Clinical Chemistry, Medical Faculty, University of Cologne, Cologne, Germany.
10
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
12
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.
13
Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
14
Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. h.wikman@uke.de.

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.

SIGNIFICANCE:

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.

PMID:
25716347
DOI:
10.1158/2159-8290.CD-14-1042
[Indexed for MEDLINE]
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