MCF7 EGF, HRG stimulation

Sharing common ErbB/HER receptor signaling pathway, heregulin (HRG) induces differentiation of MCF-7 breast cancer cells while epidermal growth factor (EGF) elicits proliferation. Although the cell fate led by those two ligands was totally different, the gene expression profile in early transcription was unexpectedly qualitatively similar, suggesting that the gene expression in late transcription, not early transcription, may reflect a respect of ligand specificity. In this study, based on the data from time-course microarray of all human genes, we predicted and determined a series of transcription factors which may control HRG-specific timed-late transcription and cellular differentiation of MCF-7 cells. Validation analyses showed that one of activator protein 1 (AP-1) families appeared just after c-Fos expression, another AP-1 family partner, induced expression of another transcription factor through activation of AP-1 complex. Furthermore, expression of this transcription factors caused suppression of extracellular signal-regulated kinase (ERK) phosphorylation which is sustainedly regulated by HRG-initiated ErbB signaling. Overall, our analysis indicated an importance of formation of timed-transcriptional regulatory network and its function to control upstream signaling pathway through negative feedback for cellular differentiation.

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Saeki Y, Endo T, Ide K, Nagashima T, Yumoto N, Toyoda T, Suzuki H, Hayashizaki Y, Sakaki Y, Okada-Hatakeyama M