TGFβ 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-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.

Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network

“…The elevation of FOS-like antigen 1 expression is positively correlated with the progression of perihilar cholangiocarcinoma [ 25 ]. More importantly, a prior research illustrated that FOS was involved in gene expression regulated by TGF-β [ 26 ]. Furthermore, the tumor-promoting effects of TGF-β signaling pathway have been reported in cholangiocarcinoma [ 15 ].…”

TRAF4/6 Is Needed for CD44 Cleavage and Migration via RAC1 Activation

“…Human colon cancer HCT-116 and CACO-2 cells were grown in McCoy′s 5a medium (Sigma-Aldrich Sweden AB, Stockholm, Sweden) and in Minimum Essential Medium Eagle (Sigma-Aldrich Sweden AB, Stockholm, Sweden), respectively (both cell lines were kindly provided by Dr I. Ferby, Uppsala University, being purchased from ATCC). Ras-transformed premalignant MCF10AneoT (MII) cells [ 59 ] were cultured in DMEM/F12 (Gibco, Life Technologies Europe BV, Stockholm, Sweden). Cells were maintained at 5% CO 2 in a humidified atmosphere at 37 °C.…”

Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic

“…In this study, we identified yet another CSC marker; COL17A1, a novel TP53 target [ 42 ] and a frequently mutating gene in breast cancer ( Table S3 ), is known to be involved in the regulation of both cell migration and invasion [ 42 , 43 ]. Moreover, additional markers identified include EGFR, AP-1, p63, and TGF-β, as their pro-oncogenic functions regulate breast cancer invasiveness, and therefore, these can be exploited as therapeutic targets in breast cancer [ 44 ]. The p53 family member p63 is a transcriptional regulator of epithelial development and differentiation; moreover, p63 is also involved in the transcriptional regulation of EGFR genes [ 44 ], frequently mutating genes in breast cancer ( Table S3 ).…”

“…Moreover, additional markers identified include EGFR, AP-1, p63, and TGF-β, as their pro-oncogenic functions regulate breast cancer invasiveness, and therefore, these can be exploited as therapeutic targets in breast cancer [ 44 ]. The p53 family member p63 is a transcriptional regulator of epithelial development and differentiation; moreover, p63 is also involved in the transcriptional regulation of EGFR genes [ 44 ], frequently mutating genes in breast cancer ( Table S3 ). In addition, in this study, we identified TP63, an EMT gene, as a member of a 13-gene signature for overall survival.…”