Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways.
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.
Gallego
Marta I
MI
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0822, USA. mi.gallego@ciemat.es
Bierie
Brian
B
Hennighausen
Lothar
L
D000818:Animals; D018196:Carcinoma, Adenosquamous / Q000209:etiology / Q000378:metabolism / Q000556:secondary*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008894:Milk Proteins; D015534:Trans-Activators; D051176:beta Catenin; C024471:whey acidic proteins; D017228:Hepatocyte Growth Factor