A mutant p53/miR-30d axis controls cell polarity in Breast Cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) characterized by highly aggressive phenotype, unfavorable prognosis and lack of specific therapy. At the molecular level TNBC resembles basal-like subtype of BC, characterized by high prevalence of missense point mutations in the TP53 gene, one of the most frequent genetic events in human cancers. Mutant-p53 proteins on one hand lose wild-type tumor suppressive functions but, on the other, acquire oncogenic properties (†œgain-of-function†�, GOF) that actively contribute to tumorigenesis. Studies in aggressive breast cancer-derived cell lines underscored a central role of mut-p53 in cell-polarity disruption and acquisition of highly aggressive phenotype. Increasing knowledge about the mechanism that regulates the establishment and maintenance of cell polarity, have reveled its important contributions in preventing acquisition of tumorigenic features, but it is still challenging to understand how cancer genes and pathway influence epithelial architecture. Despite the increasing knowledge of mut-p53 functions, little is known about microRNAs associated with mut-p53. Here we investigated whether mut-p53 GOFs exerted in TNBC could be in part mediated by miRNAs whose expression is promoted mut-p53. In MDA-MB-231 (TNBC cells harboring endogenous mut-p53) we performed a screening of miRNAs previously described to be overexpressed in BC and other solid tumors. Among miRNAs positively regulated by mut-p53 we identified miR-30d. Results of further experiments suggest that mut-p53/miR-30d axis plays an important role in inducing epithelial cell polarity disruption and causes aggressive cancer phenotypes, such as cellular migration and invasion. We also identified and validated targets of the mutp53/miR-30d axis that could be involved in mediating their biological effects. In particular we identified DLG5 as a key gene whose suppression by mut-p53/miR-30d seems to be correlated with epithelial cell polarity disruption and causes cancer aggressiveness. We propose that understanding pathways affected by miR-30d will provide new insights that can be exploited in discovery of novel therapeutic targets and diagnostic markers in TNBC.