Research ArticleCancer

Ras and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional program

Sci. Signal.  23 Aug 2016:
Vol. 9, Issue 442, pp. ra84
DOI: 10.1126/scisignal.aag3232

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Metastatic convergence at ΔNp63

The p53 family of transcription factors, which includes p53, p63, and p73, is implicated in both tumor-suppressive and tumorigenic functions. Activation of the Ras and transforming growth factor–β (TGF-β) signaling pathways are similarly enigmatic with both tumor-suppressing and tumor-promoting activity. Deciphering their roles in various stages of tumor development is critical to developing targeted therapeutics. Vasilaki et al. found that these factors are all connected in the development of some cancers. Activation of Ras or TGF-β signaling stimulated the transcriptional activity of the isoform ΔNp63 in breast or squamous cancer cells by suppressing the abundance of the mutant form of p53, an inhibitor of ΔNp63 and also a feature implicated in early tumorigenesis. Increased abundance of ΔNp63 in breast cancer cells stimulated metastatic behaviors in culture and in mice and correlated with poor prognosis in patients with mutant p53–positive tumors. These findings provide some insight into dichotic, stage-specific signals in tumorigenesis. Identification of this downstream common effector could also offer new therapeutic opportunities for some advanced Ras- or TGF-β–driven tumors.

Abstract

The p53 family of transcription factors includes p63, which is a master regulator of gene expression in epithelial cells. Determining whether p63 is tumor-suppressive or tumorigenic is complicated by isoform-specific and cellular context–dependent protein associations, as well as antagonism from mutant p53. ΔNp63 is an amino-terminal–truncated isoform, that is, the predominant isoform expressed in cancer cells of epithelial origin. In HaCaT keratinocytes, which have mutant p53 and ΔNp63, we found that mutant p53 antagonized ΔNp63 transcriptional activity but that activation of Ras or transforming growth factor–β (TGF-β) signaling pathways reduced the abundance of mutant p53 and strengthened target gene binding and activity of ΔNp63. Among the products of ΔNp63-induced genes was dual-specificity phosphatase 6 (DUSP6), which promoted the degradation of mutant p53, likely by dephosphorylating p53. Knocking down all forms of p63 or DUSP6 and DUSP7 (DUSP6/7) inhibited the basal or TGF-β–induced or epidermal growth factor (which activates Ras)–induced migration and invasion in cultures of p53-mutant breast cancer and squamous skin cancer cells. Alternatively, overexpressing ΔNp63 in the breast cancer cells increased their capacity to colonize various tissues upon intracardiac injection in mice, and this was inhibited by knocking down DUSP6/7 in these ΔNp63-overexpressing cells. High abundance of ΔNp63 in various tumors correlated with poor prognosis in patients, and this correlation was stronger in patients whose tumors also had a mutation in the gene encoding p53. Thus, oncogenic Ras and TGF-β signaling stimulate cancer progression through activation of the ΔNp63 transcriptional program.

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