MiR-18a-5p attenuates HER2-positive breast cancer development by regulating PI3K/AKT pathway

Objective: Human epidermal growth factor receptor 2 positive (HER2⁺) breast Cancer (BC) is associated with poor prognosis. This study aimed to elucidate the role of miR-18a-5p in regulation of HER2⁺-BC progression along with its mechanism of action.

Methods: The expression of miR-18a-5p and HER2 in BC cells and tissues was analyzed using quantitative Real-Time PCR while protein level expression of Akt Serine/Threonine Kinase 1 (Akt), phosphorylated Akt (p-AKT), Phosphatidylinositol 3-kinase (PI3K), phosphorylated-PI3K (p-PI3K), and HER2 were assessed by western blotting. Cell Counting Kit-8, wound healing, and cell adhesion assays were used for in vitro analysis along with xenograft tumor model construction for in vivo analysis. Pearson correlation analysis and dual-luciferase reporter (DLR) assays were used to ascertain the targeting association between miR-18a-5p and HER2.

Results: There was a downregulation of miR-18a-5p expression in the BC tissues and cells. Functionally, overexpression of miR-18a-5p prevented BC cells from proliferation, adherence, migration, and activation of the P-PI3K/P-AKT pathway. In vivo experiment revealed that tumor growth was suppressed when miR-18a-5p was overexpressed. In BC, HER2 overexpression increased cell proliferation, cell-cell adhesion, migration, and P-PI3K/P-AKT signaling, but overexpression of miR-18a-5p reversed this effect because of the target relationship between miR-18a-5p and HER2.

Conclusion: miR-18a-5p inhibits HER2⁺ BC progression by targeting HER2 to inhibit PI3K/Akt pathway activation. A theoretical foundation for the identification of new therapeutic targets for HER2⁺ BC may be provided by the miR-18a-5p - HER2 axis.

Breast cancer; HER2; MiR-18a-5p; PI3K/AKT pathway.