Ror2-mediated alternative Wnt signaling regulates cell fate and adhesion during mammary tumor progression

Oncogene. 2017 Oct 26;36(43):5958-5968. doi: 10.1038/onc.2017.206. Epub 2017 Jun 26.


Cellular heterogeneity is a common feature in breast cancer, yet an understanding of the coexistence and regulation of various tumor cell subpopulations remains a significant challenge in cancer biology. In the current study, we approached tumor cell heterogeneity from the perspective of Wnt pathway biology to address how different modes of Wnt signaling shape the behaviors of diverse cell populations within a heterogeneous tumor landscape. Using a syngeneic TP53-null mouse model of breast cancer, we identified distinctions in the topology of canonical Wnt β-catenin-dependent signaling activity and non-canonical β-catenin-independent Ror2-mediated Wnt signaling across subtypes and within tumor cell subpopulations in vivo. We further discovered an antagonistic role for Ror2 in regulating canonical Wnt/β-catenin activity in vivo, where lentiviral shRNA depletion of Ror2 expression augmented canonical Wnt/β-catenin signaling activity across multiple basal-like models. Depletion of Ror2 expression yielded distinct phenotypic outcomes and divergent alterations in gene expression programs among different tumors, despite all sharing basal-like features. Notably, we uncovered cell state plasticity and adhesion dynamics regulated by Ror2, which influenced Ras Homology Family Member A (RhoA) and Rho-Associated Coiled-Coil Kinase 1 (ROCK1) activity downstream of Dishevelled-2 (Dvl2). Collectively, these studies illustrate the integration and collaboration of Wnt pathways in basal-like breast cancer, where Ror2 provides a spatiotemporal function to regulate the balance of Wnt signaling and cellular heterogeneity during tumor progression.

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Adhesion / genetics
  • Dishevelled Proteins / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • Receptor Tyrosine Kinase-like Orphan Receptors / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Wnt Signaling Pathway / genetics
  • beta Catenin / genetics
  • rho GTP-Binding Proteins / genetics*
  • rho-Associated Kinases / genetics*
  • rhoA GTP-Binding Protein


  • Dishevelled Proteins
  • Dvl2 protein, mouse
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Ror2 protein, mouse
  • Rock1 protein, mouse
  • rho-Associated Kinases
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein