FRA-1 as a driver of tumour heterogeneity: a nexus between oncogenes and embryonic signalling pathways in cancer

Abstract

Tumour heterogeneity is a major factor undermining the success of therapies targeting metastatic cancer. Two major theories are thought to explain the phenomenon of heterogeneity in cancer--clonal evolution and cell plasticity. In this review, we examine a growing body of work implicating the transcription factor FOS-related antigen 1 (FRA-1) as a central node in tumour cell plasticity networks, and discuss mechanisms regulating its activity in cancer cells. We also discuss evidence from the FRA-1 perspective supporting the notion that clonal selection and cell plasticity represent two sides of the same coin. We propose that FRA-1-overexpressing clones featuring high plasticity undergo positive selection during consecutive stages of multistep tumour progression. This model underscores a potential mechanism through which tumour cells retaining elevated levels of plasticity acquire a selective advantage over other clonal populations within a tumour.

Figure 1. Mechanisms regulating FRA-1 accumulation in tumour cells.

Transcription of the FRA-1 gene, FOSL1, is regulated by various transcription factors that bind to its promoter and/or intron 1, as well as by chromatin remodelling factors. Once transcribed, FOSL1 transcripts can be targeted for degradation by several species of miRNAs. The FRA-1 protein itself is highly labile and is targeted to the proteasome for destruction through an ubiquitin-independent route. This process is antagonized by phosphorylation of FRA-1 by MEK-ERK-RSK or PKCθ-SPAK1 induced.

Figure 2. Interactions between FRA-1 and EMT-TF/miR loops.

(a) FRA-1 can directly regulate transcription of ZEB proteins, which control cell plasticity by operating in a double-negative feedback loop with miR-200 family members. Expression of FRA-1 is repressed by p53-inducible miR-34, which acts in a double-negative feedback loop with SNAIL1. (b) Identification of a potential miR-200 recognition element in the 3′-UTR of FOSL1.

Figure 3. Contribution of FRA-1 to tumour cell plasticity control during cancer progression.

In this model, positive selection of tumour cell clones overexpressing FRA-1 during cancer progression is predicted to generate EMT-committed cell populations. The enhanced plasticity of these populations may then contribute to tumour heterogeneity, by enabling epithelial or mesenchymal phenotypes to be adopted in response to micro-environmental cues.