Priority Research Papers:
ΔNp63 drives metastasis in breast cancer cells via PI3K/CD44v6 axis
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Simone Di Franco1,*, Alice Turdo1,*, Antonina Benfante1, Maria L. Colorito1,2, Miriam Gaggianesi1, Tiziana Apuzzo1, Raju Kandimalla3, Aurora Chinnici1, Daniela Barcaroli4, Laura Rosa Mangiapane1, Giuseppe Pistone5, Salvatore Vieni1, Eliana Gulotta1, Francesco Dieli6, Jan Paul Medema3, Giorgio Stassi1, Vincenzo De Laurenzi2 and Matilde Todaro6,7
1 Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy
2 Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University “G. d’Annunzio” Chieti-Pescara, CESI-MeT, Chieti, Italy
3 Laboratory for Experimental Oncology and Radiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
4 DISPUTer, University “G. d’Annunzio” Chieti-Pescara, Chieti, Italy
5 Department of DIBIMIS, Dermatology Section, University of Palermo, Palermo, Italy
6 Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy
7 DiBiMIS, University of Palermo, Palermo, Italy
* These authors have contributed equally to this work
Matilde Todaro, email:
Vincenzo De Laurenzi, email:
Keywords: breast cancer initiating cells, p63, PI3K/AKT pathway, CD44v6, metastasis
Received: June 20, 2016 Accepted: July 22, 2016 Published: August 02, 2016
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.
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