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Novel common integration sites targeted by mouse mammary tumor virus insertion in mammary tumors have oncogenic

Hyoung H Kim1, A Pieter J van den Heuvel, John W Schmidt

  • 1Department of Microbiology/Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Plos One
|November 17, 2011
PubMed

Insights

Mouse mammary tumor virus (MMTV) causes cancer by integrating near growth-control genes. This study identified novel MMTV integration sites, revealing new genes like Tcf7l2, Antxr1/Tem8, and Arhgap18 involved in mammary tumor development.

Area of Science:

  • Oncology
  • Virology
  • Genetics

Background:

  • Non-acute transforming retroviruses, such as mouse mammary tumor virus (MMTV), induce cancer via insertional mutagenesis near growth-regulating genes.
  • MMTV is known to activate Wnt and Fgf pathways in mammary tumors, but many integration sites remain unidentified.

Purpose of the Study:

  • To identify novel common MMTV proviral integration sites (CISs) in MMTV-induced mammary tumors.
  • To investigate the oncogenic potential of newly identified CISs in mammary gland cells.

Main Methods:

  • High-throughput screening was employed to identify common proviral integration sites in MMTV-induced tumors from C3H/HeN and BALB/c mice.
  • The expression of identified genes (Tcf7l2, Antxr1/Tem8, Arhgap18) was analyzed in normal murine mammary gland cells.
  • Cellular transformation was assessed using three-dimensional culture models.

Main Results:

  • Novel MMTV CISs were identified, including Tcf7l2, Antxr1/Tem8, and Arhgap18, in addition to known Wnt and Fgf pathway members.
  • Expression of Tcf7l2, Antxr1/Tem8, and Arhgap18 in mammary cells altered growth kinetics and induced morphological transformation in 3D culture.
  • Tcf7l2 and Antxr1/Tem8 expression sensitized cells to WNT ligand stimulation.

Conclusions:

  • MMTV-induced insertional mutagenesis is a valuable tool for discovering novel cancer-associated genes.
  • Tcf7l2, Antxr1/Tem8, and Arhgap18 are identified as potential oncogenes implicated in mammary tumorigenesis.
  • These findings highlight the role of MMTV CISs in identifying genes relevant to human breast cancer.

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