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.
Highlights
IntroductionThe p63 gene encodes six different isoforms, based on the presence of an amino-terminal trans-activation domain (TAp63) or its absence (ΔNp63), which can undergo alternative splicing at the 3’ end of the gene to generate the α, β and γ isoforms [4, 5]
The development of epithelial tissue is a finely regulated process that involves several transcriptional factors [1]. p63, a p53 homolog, plays a key role in the generation of all the stratified squamous epithelia and their derivatives, including breast [2, 3].The p63 gene encodes six different isoforms, based on the presence of an amino-terminal trans-activation domain (TAp63) or its absence (ΔNp63), which can undergo alternative splicing at the 3’ end of the gene to generate the α, β and γ isoforms [4, 5]
We show that breast cancer sphere cells (BCSCs), known to be enriched in cells with cancer initiating/stem-like features [16], are characterized by the expression of ΔNp63, which is crucial for the induction of an EMT programme, increasing the ability of breast cancer cells to migrate and form distant metastasis, through the activation of PI3K/AKT pathway and CD44v6 expression
Summary
The p63 gene encodes six different isoforms, based on the presence of an amino-terminal trans-activation domain (TAp63) or its absence (ΔNp63), which can undergo alternative splicing at the 3’ end of the gene to generate the α, β and γ isoforms [4, 5]. Their structure suggests that TAp63 and ΔNp63 have distinct and opposing functions. P63 KO mice showed alterations of all stratified epithelia as well as of epithelial appendages, including the mammary gland The interpretation of these results about the role of p63 in epithelial development is still controversial and different models have been proposed. A third model attempts to reconcile the previous ones, suggesting that ΔNp63 is essential for the maintenance of the progenitor population while TAp63 is necessary to allow complete differentiation [6,7,8,9]
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