MicroRNA in combination with HER2-targeting drugs reduces breast cancer cell viability in vitro

Lisa Svartdal Normann,Mads Haugland Haugen,Suvi-Katri Leivonen,Miriam Ragle Aure,Vesa Hongisto,Gunhild Mari Mælandsmo,Kristine Kleivi Sahlberg,Vessela N Kristensen

doi:10.1038/s41598-021-90385-2

Abstract

HER2-positive (HER2 +) breast cancer patients that do not respond to targeted treatment have a poor prognosis. The effects of targeted treatment on endogenous microRNA (miRNA) expression levels are unclear. We report that responsive HER2 + breast cancer cell lines had a higher number of miRNAs with altered expression after treatment with trastuzumab and lapatinib compared to poorly responsive cell lines. To evaluate whether miRNAs can sensitize HER2 + cells to treatment, we performed a high-throughput screen of 1626 miRNA mimics and inhibitors in combination with trastuzumab and lapatinib in HER2 + breast cancer cells. We identified eight miRNA mimics sensitizing cells to targeted treatment, miR-101-5p, mir-518a-5p, miR-19b-2-5p, miR-1237-3p, miR-29a-3p, miR-29c-3p, miR-106a-5p, and miR-744-3p. A higher expression of miR-101-5p predicted better prognosis in patients with HER2 + breast cancer (OS: p = 0.039; BCSS: p = 0.012), supporting the tumor-suppressing role of this miRNA. In conclusion, we have identified miRNAs that sensitize HER2 + breast cancer cells to targeted therapy. This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2 + breast cancers.

Highlights

human epidermal growth factor receptor 2 (HER2)-positive (HER2 +) breast cancer patients that do not respond to targeted treatment have a poor prognosis
Breast cancer, multiple pre-clinical and prognostic implications of miRNAs have been reported. These include the identification of miRNAs essential for HER2-positive breast cancer cell growth[7], miRNAs that regulate estrogen receptor signaling[8], miRNAs that increase the proliferation of breast cancer cell lines[9], miRNAs acting as metastasis suppressors in breast cancer[10], miRNAs positively regulating cell migration and invasion[11], and previously we linked a high expression level of miR-29c to disease specific s urvival[12]
We wanted to study to what extent treatment with HER2-targeted drugs impact the endogenous miRNA expression levels in breast cancer cells

Summary

Introduction

HER2-positive (HER2 +) breast cancer patients that do not respond to targeted treatment have a poor prognosis. We have identified miRNAs that sensitize HER2 + breast cancer cells to targeted therapy This indicates the potential of combining targeted drugs with miRNAs to improve current treatments for HER2 + breast cancers. A phase I dose escalating trial using TargomiRs (minicells loaded with miR-16 mimics) in malignant pleural mesothelioma and non-small cell lung cancer patients concluded on an acceptable safety profile and early signs of therapeutic a ctivity[19] (NCT02369198). This latter example lays a promising ground for further work on miRNA therapy

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