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

ABSTRACT: Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-? (TGF?)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGF? critically rely on epidermal growth factor receptor (EGFR) activation and expression of the ?N isoform of transcriptional regulator p63. EGFR and ?Np63 enabled and/or potentiated the activation of a subset of TGF?-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGF?- 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? induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGF?-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?. These cooperative pro-oncogenic functions of EGFR, AP-1, p63, and TGF? 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.

SUBMITTER: Sundqvist A 

PROVIDER: S-EPMC7253358 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature