Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic acid–induced 2

Stefan Werner, Benedikt Brors, Julia Eick, Elsa Marques, Vivian Pogenberg, Annabel Parret, Dirk Kemming, Antony W. Wood, Henrik Edgren, Hans Neubauer, Thomas Streichert, Sabine Riethdorf, Upasana Bedi, Irene Baccelli, Manfred Jucker, Roland Eils, Tanja Fehm, Andreas Trumpp, Steven A. Johnsen, Juha KlefstromMatthias Wilmanns, Volkmar Muller, Klaus Pantel, Harriet Wikman

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)506-519
Number of pages14
JournalCancer discovery
Issue number5
StatePublished - May 2015

ASJC Scopus subject areas

  • Oncology


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