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.