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

Oncogene volume 22, pages 8498–8508 (2003)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Cardiff for histopathological characterization, Sandra Canelles for technical support, Dr La Rochelle for mouse HGF cDNA; MIG was a recipient of a fellowship from the Susan G Komen Breast Cancer Foundation grant number 9859.

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  1. Marta I Gallego

    Present address: CIEMAT, Av. Complutense 22, Edifico 7, Madrid, 28040, Spain

Authors and Affiliations

  1. Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892-0822, MD, USA

    Marta I Gallego, Brian Bierie & Lothar Hennighausen

  2. Project on Breast Cancer, Fundación Marcelino Botín, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, 28042, Spain

    Marta I Gallego

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  1. Marta I Gallego
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Correspondence to Marta I Gallego.

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Gallego, M., Bierie, B. & Hennighausen, L. Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways. Oncogene 22, 8498–8508 (2003). https://doi.org/10.1038/sj.onc.1207063

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