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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Andermarcher E, Surani MA, Gherardi E . (1996). Dev Genet 18: 254–266.
Atlas E, Stramwasser M, Whiskin K, Mueller CR . (2000). Oncogene 19: 1933–1940.
Ball RK, Friis RR, Schoenenberger CA, Doppler W, Groner B . (1988). EMBO J 7: 2089–2095.
Bell AW, Jiang JG, Chen Q, Liu Y, Zarnegar R . (1998). J Biol Chem 273: 6900–6908.
Bladt F, Riethmacher D, Isenmann S, Aguzzi A, Birchmeier C . (1995). Nature 376: 768–771.
Boccaccio C, Ando M, Tamagnome L, Bardelli A, Michieli P, Battistini C et al. (1998). Nature 391: 285–288.
Braunstein J, Brutsaert S, Olson R, Schindler C . (2003). J Biol Chem 278: 34133–34140.
Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L et al. (1992). J Cell Biol 119: 629–641.
Byers S, Park M, Sommers C, Seslar S . (1994). Breast Cancer Res Treat 31: 203–215.
Darnell Jr JE . (2002). Nat Rev Cancer 2: 740–749.
Di Renzo MF, Olivero M, Ferro S, Prat M, Bongarzone I, Pilotti S et al. (1992). Oncogene 7: 2549–2553.
Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L et al. (1995a). Clin Cancer Res 1: 147–154.
Di Renzo MF, Olivero M, Katsaros D, Crepaldi T, Gaglia P, Zola P et al. (1994). Int J Cancer 58: 658–662.
Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR . (1995b). Cancer Res 55: 1129–1138.
Dolled-Filhart M, Camp RL, Kowalski DP, Smith BL, Rimm DL . (2003). Clin Cancer Res 9: 594–600.
Elliott BE, Hung WL, Boag AH, Tuck AB . (2002). Can J Physiol Pharmacol 80: 91–102.
Gallego MI, Bierie B, Hennighausen L . (2003). Oncogene 22: 8498–8508.
Horvath CM, Wen Z, Darnell JEJ . (1995). Genes Dev 9: 984–994.
Hung W, Elliott B . (2001). J Biol Chem 276: 12395–12403.
Jiang JG, DeFrances MC, Machen J, Johnson C, Zarnegar R . (2000a). Biochem Biophys Res Commun 272: 882–886.
Jiang JG, Gao B, Zarnegar R . (2000b). Oncogene 19: 2786–2790.
Jiang JG, Johnson C, Zarnegar R . (2001). J Biol Chem 276: 25049–25056.
Jiang J-G, Zarnegar R . (1997). Mol Cell Biol 17: 5758–5770.
Jin L, Fuchs A, Schnitt SJ, Yao Y, Joseph A, Lamszus K et al. (1996). Cancer 79: 749–760.
Klosek SK, Nakashiro K, Hara S, Li C, Shintani S, Hamakawa H . (2004). Oncol Rep 12: 293–296.
Liu Y, Beedle AB, Lin L, Bell AW, Zarnegar R . (1994a). Mol Cell Biol 14: 7046–7058.
Liu Y, Michalopoulos GK, Zarnegar R . (1994b). J Biol Chem 269: 4152–4160.
Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP . (1995). Nature 375: 577–581.
Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J et al. (2002). Oncogene 21: 2000–2008.
Olivero M, Rizzo M, Madeddu R, Casadio C, Pennacchietti S, Nicotra MR et al. (1996). Br J Cancer 74: 1862–1868.
Paz K, Socci ND, van Nimwegen E, Viale A, Darnell JE . (2004). Oncogene 23: 8455–8463.
Plaschke-Schlutter A, Behrens J, Gherardi E, Birchmeier W . (1995). J Biol Chem 270: 830–836.
Rahimi N, Hung W, Saulnier R, Tremblay E, Elliott B . (1998). J Biol Chem 273: 33714–33721.
Rahimi N, Tremblay E, McAdam L, Park M, Schwall R, Elliott B . (1996). Cell Growth Differ 7: 263–270.
Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M et al. (1995). Nature 373: 699–702.
Seidel HM, Milocco LH, Lamb P, Darnell JEJ, Stein RB, Rosen J . (1995). Proc Natl Acad Sci USA 92: 3041–3045.
Siegfried JM, Weissfeld LA, Singh-Kaw P, Weyant RJ, Testa JR, Landreneau RJ . (1997). Cancer Res 57: 433–439.
Tomida M, Saito T . (2004). Oncogene 23: 679–686.
Trovato M, Vitarelli E, Grosso M, Alesci S, Benvenga S, Trimarchi F et al. (2004). Eur J Histochem 48: 291–297.
Tuck AB, Park M, Sterns EE, Boag A, Elliott BE . (1996). Am J Path 148: 225–232.
Turkson J, Bowman T, Adnane J, Zhang Y, Djeu JY, Sekharam M et al. (1999). Mol Cell Biol 19: 7519–7528.
Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R . (1998). Mol Cell Biol 18: 2545–2552.
Vultur A, Cao J, Arulanandam R, Turkson J, Jove R, Greer P et al. (2004). Oncogene 23: 2600–2616.
Wang Y, Selden AC, Morgan N, Stamp GW, Hodgson HJ . (1994). Am J Path 144: 675–682.
Watson CJ . (2001). J Mamm Gland Biol Neoplasia 6: 115–127.
Yamashita J, Ogawa M, Yamashita S, Nomura K, Kuramoto M, Saishoji T et al. (1994). Cancer Res 54: 1630–1633.
Yang J, Chatterjee-Kishore M, Staugaitis SM, Nguyen H, Schlessinger K, Levy DE et al. (2005). Cancer Res 65: 939–947.
Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J et al. (1995). Science 269: 81–83.
Yuan ZL, Guan YJ, Chatterjee D, Chin YE . (2005). Science 307: 269–273.
Zhang YW, Wang LM, Jove R, Vande Woude GF . (2002). Oncogene 21: 217–226.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209306
Keywords
This article is cited by
-
The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer
Molecular Diagnosis & Therapy (2016)
-
Profiling phospho-signaling networks in breast cancer using reverse-phase protein arrays
Oncogene (2013)
-
HGF/c-met/Stat3 signaling during skin tumor cell invasion: indications for a positive feedback loop
BMC Cancer (2011)
-
PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo
Breast Cancer Research and Treatment (2011)
-
Prostate tumor progression is mediated by a paracrine TGF-β/Wnt3a signaling axis
Oncogene (2008)