Apc mutation enhances PyMT-induced mammary tumorigenesis

PLoS One. 2011;6(12):e29339. doi: 10.1371/journal.pone.0029339. Epub 2011 Dec 22.

Abstract

The Adenomatous Polyposis Coli (APC) tumor suppressor gene is silenced by hypermethylation or mutated in up to 70% of human breast cancers. In mouse models, Apc mutation disrupts normal mammary development and predisposes to mammary tumor formation; however, the cooperation between APC and other mutations in breast tumorigenesis has not been studied. To test the hypothesis that loss of one copy of APC promotes oncogene-mediated mammary tumorigenesis, Apc(Min/+) mice were crossed with the mouse mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) or MMTV-c-Neu transgenic mice. In the PyMT tumor model, the Apc(Min/+) mutation significantly decreased survival and tumor latency, promoted a squamous adenocarcinoma phenotype, and enhanced tumor cell proliferation. In tumor-derived cell lines, the proliferative advantage was a result of increased FAK, Src and JNK signaling. These effects were specific to the PyMT model, as no changes were observed in MMTV-c-Neu mice carrying the Apc(Min/+) mutation. Our data indicate that heterozygosity of Apc enhances tumor development in an oncogene-specific manner, providing evidence that APC-dependent pathways may be valuable therapeutic targets in breast cancer. Moreover, these preclinical model systems offer a platform for dissection of the molecular mechanisms by which APC mutation enhances breast carcinogenesis, such as altered FAK/Src/JNK signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Polyomavirus Transforming / immunology*
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Genes, APC*
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation*
  • Wnt Proteins / metabolism
  • beta Catenin / metabolism

Substances

  • Antigens, Polyomavirus Transforming
  • Wnt Proteins
  • beta Catenin