title: ΔNp63 drives metastasis in breast cancer cells via PI3K/CD44v6 axis.
abstract: 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.
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Simone
authors: S
authors: Di Franco
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Alice
authors: A
authors: Turdo
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Antonina
authors: A
authors: Benfante
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.|Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, CESI-MeT, Chieti, Italy.
authors: Maria L
authors: ML
authors: Colorito
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Miriam
authors: M
authors: Gaggianesi
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Tiziana
authors: T
authors: Apuzzo
authors: Laboratory for Experimental Oncology and Radiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Raju
authors: R
authors: Kandimalla
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Aurora
authors: A
authors: Chinnici
authors: DISPUTer, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.
authors: Daniela
authors: D
authors: Barcaroli
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Laura Rosa
authors: LR
authors: Mangiapane
authors: Department of DIBIMIS, Dermatology Section, University of Palermo, Palermo, Italy.
authors: Giuseppe
authors: G
authors: Pistone
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Salvatore
authors: S
authors: Vieni
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Eliana
authors: E
authors: Gulotta
authors: Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.
authors: Francesco
authors: F
authors: Dieli
authors: Laboratory for Experimental Oncology and Radiology, Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Jan Paul
authors: JP
authors: Medema
authors: Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy.
authors: Giorgio
authors: G
authors: Stassi
authors: Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" Chieti-Pescara, CESI-MeT, Chieti, Italy.
authors: Vincenzo
authors: V
authors: De Laurenzi
authors: Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Palermo, Italy.|DiBiMIS, University of Palermo, Palermo, Italy.
authors: Matilde
authors: M
authors: Todaro
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment
chemical_list: C112697:CD44v6 antigen; C081876:CKAP4 protein, human; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: CD44v6; PI3K/AKT pathway; breast cancer initiating cells; metastasis; p63