Abstract
Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-β (TGFβ)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGFβ critically rely on epidermal growth factor receptor (EGFR) activation and expression of the ΔN isoform of transcriptional regulator p63. EGFR and ΔNp63 enabled and/or potentiated the activation of a subset of TGFβ-inducible invasion/migration-associated genes, e.g., ITGA2, LAMB3, and WNT7A/B, and enhanced the recruitment of SMAD2/3 to these genes. The TGFβ- 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 TGFβ induction of AP-1 proteins and, in particular, FOS family members. Ectopic overexpression of FOS could counteract the decrease in TGFβ-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 TGFβ. These cooperative pro-oncogenic functions of EGFR, AP-1, p63, and TGFβ 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.
Highlights
Transforming growth factor-β (TGFβ)-induced signaling has both positive and negative functions in cancer; in late
TGFβ-induced invasion in the presence of epidermal growth factor (EGF) was inhibited both by the epidermal growth factor receptor (EGFR) kinase inhibitor lapatinib and by the TGFβRI kinase (ALK5) inhibitor SB505124 (Fig. 1b)
We examined the effect of EGF on the binding of SMAD2/3 to representative SMAD binding regions, which we had previously identified by chromatin immunoprecipitation (ChIP) sequencing [32]
Summary
Transforming growth factor-β (TGFβ)-induced signaling has both positive and negative functions in cancer; in late. TGFβ can become a strong tumor promoter in cancer cells that have become insensitive to TGFβ-induced growth inhibition by MYC activation and other cell cycle defects In particular this is the case in the presence of additional pro-oncogenic signals, such as high levels of active EGFR, mutant RAS and WNTβ-CATENIN signaling [4,5,6,7]. Essential for the specificity are the interactions of SMADs with lineage-determining and signal-driven transcription factors, chromatin-remodeling factors, co-activators, and co-repressors, which increase SMAD DNA binding and transactivating potential In addition to these interactions, multiple other layers of regulation influence the intensity and duration of TGFβ signaling, and thereby define the specificity of the response [7, 12]. We present novel mechanistic insight into the pro-oncogenic EGF-TGFβ-p63-AP-1 interplay in breast cancer cells
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