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  • Original Article
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A novel activating function of c-Src and Stat3 on HGF transcription in mammary carcinoma cells

Abstract

In the normal breast, hepatocyte growth factor (HGF) is primarily expressed by stromal cells, and stimulates in a paracrine manner epithelial cells expressing the HGF receptor (Met). In invasive human breast carcinomas, HGF and Met are frequently overexpressed, possibly establishing an autocrine HGF/Met loop that promotes tumour cell invasion. However, the mechanisms leading to autocrine HGF expression in carcinoma cells are not known. We previously demonstrated a cooperative effect between c-Src and Stat3 in the activation of HGF transcription in mammary carcinoma cells. The present report defines a novel Stat3 consensus site at nt −95 in the HGF promoter that is highly conserved in human and mouse, and is required for c-Src and Stat3 to activate HGF transcription in breast epithelial cells. DNA–protein binding studies demonstrated high affinity binding of a Stat3-containing complex to the nt −95 site. Endogenous Stat3 binding to this region of the HGF promoter in carcinoma cells expressing HGF was demonstrated using a chromatin immunoprecipitation assay. In addition, coexpression of Stat3 and activated c-Src caused increased expression of endogenous HGF mRNA and protein and marked cell scattering in breast epithelial cells. Our results delineate a novel c-Src/Stat3-dependent mechanism that regulates HGF promoter activity, and is linked to transformation of mammary epithelial cells.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (#61799), the Canadian Breast Cancer Research Alliance (#14315) and the USAMRMC Breast Cancer Research Initiative (# DAMD17-96-I-6251). EJW and TGW were recipients of USAMRMC training fellowships (DMD17-98-8330 and DMD17-99-1-9380, respectively). We are grateful to Dr D Shalloway for providing the SRC-Y527F plasmid. Peter Cheung provided assistance in primer design and optimizing PCR and RT–PCR procedures. We thank Ms Jalna Meens for her excellent technical assistance.

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Wojcik, E., Sharifpoor, S., Miller, N. et al. A novel activating function of c-Src and Stat3 on HGF transcription in mammary carcinoma cells. Oncogene 25, 2773–2784 (2006). https://doi.org/10.1038/sj.onc.1209306

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