ΔNp63 drives metastasis in breast cancer cells via PI3K/CD44v6 axis

Simone Di Franco, Alice Turdo, Antonina Benfante, Maria L. Colorito, Miriam Gaggianesi, Tiziana Apuzzo, Raju Kandimalla, Aurora Chinnici, Daniela Barcaroli, Laura Rosa Mangiapane, Giuseppe Pistone, Salvatore Vieni, Eliana Gulotta, Francesco Dieli, Jan Paul Medema, Giorgio Stassi, Vincenzo De Laurenzi, Matilde Todaro

P63 is a transcription factor belonging to the family of p53, essential for the development and differentiation of epithelia. In recent years, it has become clear that altered expression of the different isoforms of this gene can play an important role in carcinogenesis. The p63 gene encodes for two main isoforms known as TA and ΔN p63 with different functions. The role of these different isoforms in sustaining tumor progression and metastatic spreading however has not entirely been clarified.Here we show that breast cancer initiating cells express ΔNp63 isoform that supports a more mesenchymal phenotype associated with a higher tumorigenic and metastatic potential. On the contrary, the majority of cells within the tumor appears to express predominantly TAp63 isoform. While ΔNp63 exerts its effects by regulating a PI3K/CD44v6 pathway, TAp63 modulates this pathway in an opposite fashion. As a result, tumorigenicity and invasive capacity of breast cancer cells is a balance of the two isoforms. Finally, we found that tumor microenvironmental cytokines significantly contribute to the establishment of breast cancer cell phenotype by positively regulating ΔNp63 and CD44v6 expression.