Abstract
The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.
Highlights
The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression
By performing RNA-seq (RNA-sequencing) analysis of wild-type (WT) and TAp63−/− MECs6, we found that TAp63−/−mammary epithelial cells (MECs) contained 591 long noncoding RNAs (lncRNAs) that were differentially expressed compared to WT MECs
To determine whether these mouse lncRNAs had human orthologs involved in breast cancer formation and progression, we used a locus conservation approach[12] to compare the differentially expressed mouse lncRNAs to human lncRNAs differentially expressed in the MCF10A breast cancer progression model[13,14], comprised of four cell lines: (i) MCF10A; (ii) AT1; (iii) ductal carcinoma in situ (DCIS); and (iv) CA1D
Summary
The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Multiple pathways have been found to increase cancer progression and metastasis including the activation of the PI3K/AKT pathway[2] and the gain-of-function mutation of the tumour suppressor TP533, which are the two most frequent driving mutations in a broad variety of human cancers[4]. Using breast cancer as a model system and extending our findings using a pan-cancer approach including xenograft mouse models, TCGA datasets, and 723 clinical cases, we provide molecular and functional evidence that the tumorigenic and metastatic potential of these lncRNAs is mediated by one of their interacting proteins, WDR26. Our findings identify a crucial mechanism for the activation of the AKT pathway through TAp63-regulated lncRNAs (TROLLs) and pave the way for more effective therapies against metastatic cancers with alterations in TP53 and hyperactivation of the PI3K/AKT pathway
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