Epigenetically altered miR­193a­3p promotes HER2 positive breast cancer aggressiveness by targeting GRB7.

ABSTRACT

Emerging evidence has demonstrated that microRNAs (miRNAs/miRs) have various biological functions in the development of human epidermal growth factor receptor 2 (HER2) positive breast cancer. The aim of the present study is to reveal the mechanism of miR­193a­3p inhibiting the progress of HER2 positive breast cancer. The expression of miR­193a­3p was evaluated by quantitative polymerase chain reaction (PCR). The methylation status of miR­193a­3p was evaluated by PCR and pyrosequencing analysis. Overexpression of miR­193a­3p and growth factor receptor bound protein 7 (GRB7) combined with in vitro tumorigenic assays were conducted to determine the carcinostatic capacities of miR­193a­3p in HER2 positive breast cancer cells. The association between miR­193a­3p and GRB7 was determined by luciferase reporter assay. Protein level was evaluated using western blot analysis. miR­193a­3p was downregulated in HER2 positive breast cancer cells and clinical tissues. Methylation­mediated silencing led to decreased expression of miR­193a­3p in HER2 positive breast cancer. Overexpression of miR­193a­3p could inhibit proliferation, migration and invasion of breast cancer cells. Overexpression of GRB7 could abolish this effect. miR­193a­3p could directly target the 3' untranslated region of GRB7. miR­193a­3p could directly or indirectly target extracellular signal­regulated kinase 1/2 (ERK1/2) and forkhead box M1 (FOXM1) signaling. In conclusion, it was identified that silencing of miR­193a­3p through hypermethylation can promote HER2 positive breast cancer progress by targeting GRB7, ERK1/2 and FOXM1 signaling. The function of miR­193a­3p in HER2 positive breast cancer implicates its potential application in therapy.