Abstract
Inactivation of p53 contributes significantly to the dismal prognosis of breast tumors, most notably triple-negative breast cancers (TNBCs). How the relief from p53 tumor suppressive functions results in tumor cell aggressive behavior is only partially elucidated. In an attempt to shed light on the implication of microRNAs in this context, we discovered a new signaling axis involving p53, miR-30a and ZEB2. By an in silico approach we identified miR-30a as a putative p53 target and observed that in breast tumors reduced miR-30a expression correlated with p53 inactivation, lymph node positivity and poor prognosis. We demonstrate that p53 binds the MIR30A promoter and induces the transcription of both miRNA strands 5p and 3p. Both miR-30a-5p and -3p showed the capacity of targeting ZEB2, a transcription factor involved in epithelial–mesenchymal transition (EMT), tumor cell migration and drug resistance. Intriguingly, we found that p53 does restrain ZEB2 expression via miR-30a. Finally, we provide evidence that the new p53/miR-30a/ZEB2 axis controls tumor cell invasion and distal spreading and impinges upon miR-200c expression. Overall, this study highlights the existence of a novel axis linking p53 to EMT via miR-30a, and adds support to the notion that miRNAs represent key elements of the complex network whereby p53 inactivation affects TNBC clinical behavior.
Highlights
Several lines of evidence demonstrate that inactivation of p53, the tumor suppressor most frequently involved in triple-negative breast cancers (TNBCs), affects phenotypes such as epithelial–mesenchymal transition (EMT) and cell plasticity/ stemness that contribute to tumor progression and poor response to therapies [5, 7, 34,35,36,37]
In an attempt to elucidate the mechanisms whereby p53 inactivation contributes to the aggressive behavior of Breast cancer (BC) via miRNA, we identified a novel axis involving p53, miR-30a and ZEB2
We found that the expression of miR-30a was significantly reduced in human BC samples carrying TP53 gene alterations, primarily TNBC, and inversely correlated with patients’ survival
Summary
These authors contributed : Alessandra di Gennaro, Valentina Damiano. These authors contributed : Manuela Santarosa, Roberta Maestro. Only 19% of HR-positive/luminal tumors present TP53 alterations (12% of luminal A, 29% of luminal B) that are primarily missense mutations [5] These facts support the notion that p53 contributes to TNBC/basal-like BC mostly through loss of tumor suppressive functions, rather than through gain of oncogenic activities (gain-of-function p53 mutations). P53 has been described to regulate the expression of a number of miRNAs that mediate p53 control over several biological processes including cell cycle, epithelial–mesenchymal transition (EMT) and cell plasticity, survival and metabolism [6,11,12,13,14] On these grounds we sought to investigate in deeper detail the contribution of miRNAs as mediators of p53 tumor suppressive functions in the context of TNBC/ basal-like tumors
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