The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation

Cell Rep. 2015 Apr 7;11(1):111-24. doi: 10.1016/j.celrep.2015.03.002. Epub 2015 Mar 26.


Proline-directed phosphorylation is regulated by the prolyl isomerase Pin1, which plays a fundamental role in driving breast cancer stem-like cells (BCSCs). Rab2A is a small GTPase critical for vesicle trafficking. Here, we show that Pin1 increases Rab2A transcription to promote BCSC expansion and tumorigenesis in vitro and in vivo. Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and β-catenin nuclear translocation. In cancer cells, Rab2A is activated via gene amplification, mutation or Pin1 overexpression. Rab2A overexpression or mutation endows BCSC traits to primary normal human breast epithelial cells, whereas silencing Rab2A potently inhibits the expansion and tumorigenesis of freshly isolated BCSCs. Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients. Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MAP Kinase Signaling System / genetics*
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Peptidylprolyl Isomerase / biosynthesis*
  • Peptidylprolyl Isomerase / genetics
  • Transcriptional Activation / genetics
  • rab GTP-Binding Proteins / biosynthesis
  • rab GTP-Binding Proteins / genetics*


  • NIMA-Interacting Peptidylprolyl Isomerase
  • rab GTP-Binding Proteins
  • PIN1 protein, human
  • Peptidylprolyl Isomerase

Associated data

  • GEO/GSE49971