Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways

Oncogene. 2003 Nov 20;22(52):8498-508. doi: 10.1038/sj.onc.1207063.


Overexpression of hepatocyte growth factor (HGF), also called scatter factor (SF), and its receptor c-Met are associated with poor prognosis for cancer patients. In particular, breast cancer cells can produce HGF that acts in a paracrine as well as in an autocrine manner. Therefore, HGF and c-Met are putative targets for cancer therapy. To explore HGF/c-Met signaling in breast cancer, we have generated transgenic mice expressing HGF specifically in mammary epithelium under the transcriptional control of the whey acidic protein (WAP) gene promoter. WAP-HGF transgenic females developed hyperplastic ductal trees and multifocal invasive tumors after several pregnancies, some of which progressed to lung metastases. Tumors produced HGF and displayed phosphorylated c-Met, which correlated with increased Akt as well as c-myc activation. A high growth rate, as demonstrated by Ki67 nuclear antigen staining, and a lack of progesterone receptor were characteristic of the tumors. Immunohistochemical analysis revealed areas of osteopontin (Opn) expression in WAP-HGF tumors and lung metastases in agreement with a previously reported role for Opn in invasive growth. We suggest that these mice may serve as a new breast cancer model for the evaluation of the effects of unscheduled HGF expression in breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Adenosquamous / etiology
  • Carcinoma, Adenosquamous / metabolism
  • Carcinoma, Adenosquamous / secondary*
  • Cytoskeletal Proteins / metabolism
  • Epithelium / metabolism
  • Gene Transfer Techniques*
  • Hepatocyte Growth Factor / genetics*
  • Hepatocyte Growth Factor / metabolism
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Transgenic
  • Milk Proteins / genetics
  • Neoplasm Metastasis
  • Promoter Regions, Genetic
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism
  • beta Catenin


  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Milk Proteins
  • Trans-Activators
  • beta Catenin
  • whey acidic proteins
  • Hepatocyte Growth Factor