Regulation of the interferon-gamma (IFN-γ) pathway by p63 and Δ133p53 isoform in different breast cancer subtypes

Abstract

The TP53 family consists of three sets of transcription factor genes, TP53, TP63 and TP73, each of which expresses multiple RNA variants and protein isoforms. Of these, TP53 is mutated in 25-30% of breast cancers. How TP53 mutations affect the interaction of TP53 family members and their isoforms in breast cancer is unknown. To investigate this, 3 independent breast cancer cohorts were stratified into 4 groups based on oestrogen receptor (ER) and TP53 mutation status. Using bioinformatic methodologies, principal signalling pathways associated with the expression of TP53 family members were identified. Results show an enrichment of IFN-γ signalling associated with TP63 RNA in wild type TP53 (wtTP53), ER negative (ER-) tumours and with Δ133TP53 RNA in mutant TP53 (mTP53) ER positive (ER+) tumours. Moreover, tumours with low IFN-γ signalling were associated with significantly poorer patient outcome. The predicted changes in expression of a subset of RNAs involved in IFN-γ signalling were confirmed in vitro. Our data show that different members of the TP53 family can drive transcription of genes involved in IFN-γ signalling in different breast cancer subgroups.

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

“…In agreement with the function of p63 as an essential proliferation factor (McDade et al, 2011;Senoo et al, 2007;Truong et al, 2006), epidermal development regulator (Mills et al, 1999;Yang et al, 1999), and MYC network activator (Wu et al, 2012), we find that genes commonly up-regulated by p63 significantly enrich gene sets associated with cell cycle, epidermis development, and MYC targets ( Figure 2A). In line with previous reports (Mehta et al, 2018), genes down-regulated by p63 enrich gene sets connected with interferon response ( Figure 2B). Corroborating the role of p63 in mammary stem cell activity (Chakrabarti et al, 2014) and SCC growth (Ramsey et al, 2013), we find that p63 up-and down-regulated genes enrich respective gene sets upand down-regulated in mammary stem cells ( Figure 2C) and across SCCs ( Figure 2D).…”

The Δ133p53β isoform promotes an immunosuppressive environment leading to aggressive prostate cancer

“…However, as Δ133p53 isoforms lack the transactivation domain of p53 and part of the DNA binding domain, to regulate gene transcription it seems likely that the isoforms require one or more co-factors. One of these could be p63 as shown in recent reports 34,35 . To see if any of the above genes/pathways could be regulated by Δ133p53α or Δ133p53β, we identified 318 genes defining Group A cancers that had p53/p63/p73 response elements in their promoters 36 (Spearman’s correlation coefficient ( ρ ) cutoff of >0.5, Fig.…”

“…To investigate whether any genes in these pathways are directly regulated by Δ133p53 isoforms, we again used the stable cell lines. We quantitated the transcript levels of genes involved in the IFN-γ response [interferon regulatory factor 2 ( IRF2 ), Janus Kinase 2 ( JAK2 ); IL-6 receptor subunit beta ( IL6ST ); STAT6 and C-X-C chemokine receptor type 6 ( CXCR6 )] that had previously been shown to be regulated by p63 and/or one of the Δ133p53 family members 34 . Results show that Δ133p53β expressing H1299 cell clones had elevated JAK2, STAT6 and IL6ST mRNA levels compared to control cells and Δ133p53α and Δ133p53β cell clones had elevated CXCR6 levels (Fig.…”

Silencing of Testin expression is a frequent event in spontaneous lymphomas from Trp53-mutant mice

“…The lack of Testin silencing in tissues from the Trp53-Δ122 mice suggests that Trp53-Δ122 protein can override the mechanism of silencing. A possible explanation for this comes from a report that the human Δ133p53 isoform can overcome cell growth arrest induced by p53 family members, p63 and p73 30 . Thus, p63 and/or p73 could repress Testin expression, but when Δ133p53 is over-expressed, this repression is prevented.…”