TGF beta and EGF signaling orchestrates the AP-1-and p63 transcriptional regulation of breast cancer invasiveness

Sundqvist, A.; Vasilaki, E.; Voytyuk, O.; Bai, Y.; Morikawa, M.; Moustakas, A.; Miyazono, K.; Heldin, C.H.; Dijke, P. ten; Dam, H. van

doi:doi:10.1038/s41388-020-1299-z

Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-beta (TGF beta)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGF beta critically rely on epidermal growth factor receptor (EGFR) activation and expression of the Delta N isoform of transcriptional regulator p63. EGFR and Delta Np63 enabled and/or potentiated the activation of a subset of TGF beta-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGF beta- and EGF-induced binding of SMAD2/3 and JUNB to these gene loci was accompanied by p63-SMAD2/3 and p63-JUNB complex formation. p63 and EGFR were also found to strongly potentiate TGF beta induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGF beta...Show moreActivator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-beta (TGF beta)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGF beta critically rely on epidermal growth factor receptor (EGFR) activation and expression of the Delta N isoform of transcriptional regulator p63. EGFR and Delta Np63 enabled and/or potentiated the activation of a subset of TGF beta-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGF beta- and EGF-induced binding of SMAD2/3 and JUNB to these gene loci was accompanied by p63-SMAD2/3 and p63-JUNB complex formation. p63 and EGFR were also found to strongly potentiate TGF beta induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGF beta-induced gene activation after p63 depletion. p63 is also involved in the transcriptional regulation of heparin binding (HB)-EGF and EGFR genes, thereby establishing a self-amplification loop that facilitates and empowers the pro-invasive functions of TGF beta. These cooperative pro-oncogenic functions of EGFR, AP-1, p63, and TGF beta were efficiently inhibited by clinically relevant chemical inhibitors. Our findings may, therefore, be of importance for therapy of patients with breast cancers with an activated EGFR-RAS-RAF pathway.Show less

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TGF beta and EGF signaling orchestrates the AP-1-and p63 transcriptional regulation of breast cancer invasiveness