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

• Published in: Oncogene Vol. 25; no. 19; pp. 2773 - 2784
• Main Authors: WOJCIK, E. J, SHARIFPOOR, S, MILLER, N. A, WRIGHT, T. G, WATERING, R, TREMBLAY, E. A, SWAN, K, MUELLER, C. R, ELLIOTT, B. E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 04-05-2006; Nature Publishing Group
• Subjects: Animals; Autocrine signalling; Biological and medical sciences; Breast; Breast cancer; Breast carcinoma; c-Met protein; Cancer; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells; Chromatin; Chromatin Immunoprecipitation; Electrophoretic Mobility Shift Assay; Epithelial cells; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Genes, Dominant; Gynecology. Andrology. Obstetrics; Hepatocyte growth factor; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Immunoprecipitation; Invasiveness; Luciferases - metabolism; Mammary gland; Mammary gland diseases; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Molecular and cellular biology; Molecular genetics; Mutation - genetics; Paracrine signalling; Proteins; Proto-Oncogene Proteins pp60(c-src) - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Src protein; Stat3 protein; STAT3 Transcription Factor - physiology; Stromal cells; Transcription activation; Transcription, Genetic; Transcription. Transcription factor. Splicing. Rna processing; Transcriptional Activation; Tumors; Transcription; Enzyme; Src; Transferases; breast carcinoma cells; Malignant tumor; Gene expression; Carcinogenesis; HGF expression; Mammary gland diseases; Breast carcinoma; C-Onc gene; Stat3; Mammary gland; Protein-tyrosine kinase
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209306

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.