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Rspo2/Int7 regulates invasiveness and tumorigenic properties of mammary epithelial cells

Malgorzata Klauzinska1, Bolormaa Baljinnyam, Ahmed Raafat

  • 1Oncogenetics Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, MD 20892, USA.

Journal of Cellular Physiology
|July 7, 2011
PubMed

Insights

Rspo2, a novel integration site for mouse mammary tumor virus (MMTV), modulates Wnt signaling in mammary cells. Rspo2 and Wnt1 promote distinct tumorigenic and metastatic properties, with Rspo2 driving epithelial-mesenchymal transformation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Mouse mammary tumor virus (MMTV) can integrate into the host genome, potentially affecting gene expression and contributing to tumorigenesis.
  • Wnt signaling pathways are crucial regulators of cell growth, differentiation, and development, and their dysregulation is implicated in various cancers, including breast cancer.

Purpose of the Study:

  • To investigate the role of Rspo2, a novel common integration site (CIS) for MMTV, in modulating Wnt signaling and its impact on mouse mammary epithelial cells.
  • To characterize the distinct contributions of Rspo2 and Wnt1 to mammary tumor development, epithelial-mesenchymal transformation (EMT), and metastasis.

Main Methods:

  • Co-expression of Rspo2 and Wnt1 in mouse mammary epithelial cells (HC11 transfectants).
  • Tumorigenicity assays in athymic nude mice and assessment of histological characteristics.
  • Evaluation of metastatic activity and invasive properties in three-dimensional (3D) Matrigel cultures.
  • Inhibition of Wnt/β-catenin pathway using Dickkopf-1 or short hairpin RNA targeting β-catenin.

Main Results:

  • Rspo2 modulates Wnt signaling, exhibiting distinct effects on cell growth compared to Wnt1.
  • Both Rspo2 and Wnt1 individually, and in combination, induce tumorigenesis in mice, with characteristic histological features including EMT.
  • Rspo2 and Rspo2/Wnt1 tumors display increased metastatic and invasive activities, independent of the canonical Wnt/β-catenin pathway.

Conclusions:

  • Rspo2 and Wnt1 exert context-dependent and mutually distinct effects on mammary epithelial cell growth.
  • While Rspo2 and Wnt1 can synergize in the β-catenin pathway, other mechanisms mediate the invasive properties observed in Rspo2/Wnt1 co-transfectants.
  • Rspo2 plays a significant role in MMTV-induced mammary tumorigenesis, influencing cell transformation and metastasis through pathways potentially distinct from canonical Wnt signaling.

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