In vitro microRNA expression profile alterations under HER2-targeted therapy in breast cancer

Background Targeting HER2 therapeutically represents a milestone in breast cancer therapy. Biomarkers detecting the successful HER2-directed treatment or failure are missing. MicroRNAs have proven promising biomarker potential, especially in liquid biopsies. This study analyses the biomarker-potential of microRNAs indicating q therapy response under HER2-targeted therapeutics.

Methods This study analyses intracellular and extracellular microRNA expression level alterations under six HER2-directed therapeutics: Trastuzumab, Pertuzumab, T-DM1 and their combinations with paclitaxel. The three breast cancer cell lines HS-578T, BT-474 and SK-BR-3 were analyzed using qPCR. 63 microRNAs were examined.

Results The six analyzed treatment regimen led to highly specific microRNA expression patterns in each cell lines intra- and extracellularly. Irrespective of the cell line, miR-15a was significantly downregulated in the intracellular compartment under all trastuzumab treatments, miR-181a_3p in all regimen including trastuzumab plus chemotherapy. T-DM1 led to a significant downregulation of miR-15a intra- and extracellularly. The miR-signature let-7a/let-7e/miR-17/miR-103/miR-451 showed significant regulation patterns under paclitaxel plus trastuzumab and paclitaxel plus trastuzumab and pertuzumab in the extracellular compartment across all cell lines. Multivariable analysis revealed that intracellularly miR-15a was significantly downregulated in the HER2-positive cell lines under all treatments containing trastuzumab plus chemotherapy. In the extracellular compartment, T-DM1 led to an upregulation of let-7a in HER2-positive cells and to a downregulation of miR-451 across all cell lines.

Conclusion MiR-15a is a promising intracellular and therefore tissue biomarker for trastuzumab based therapies. The miR-signature let-7a/let-7e/miR-17/miR-103/miR-451 is a potential biomarker tool in liquid biopsies to indicate therapy response for trastuzumab, let-7a and miR-451 for T-DM1.

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Publication History

Article published online:
01 June 2021