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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / metabolism
  • Amino Acid Sequence
  • Bone Marrow / pathology*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cluster Analysis
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Molecular Sequence Data
  • Neoplastic Cells, Circulating / pathology*
  • Prognosis
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proteins / chemistry
  • Proteins / genetics*
  • Proteins / metabolism
  • Reproducibility of Results
  • Sequence Alignment
  • Transcriptome


  • DNA-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Proteins
  • RAI2 protein, human
  • Alcohol Oxidoreductases
  • C-terminal binding protein