miR-21 Expression in Cancer Cells may Not Predict Resistance to Adjuvant Trastuzumab in Primary Breast Cancer

Abstract

Trastuzumab is established as standard care for patients with HER2-positive breast cancer both in the adjuvant and metastatic setting. However, 50% of the patients do not respond to the trastuzumab therapy, and therefore new predictive biomarkers are highly warranted. MicroRNAs (miRs) constitute a new group of biomarkers and their cellular expression can be determined in tumor samples by in situ hybridization (ISH) analysis. miR-21 is highly prevalent and up-regulated in breast cancer and has been linked to drug resistance in clinical and in vitro settings. To determine expression patterns of miR-21 in high-grade breast cancers, we examined miR-21 expression in 22 HER2-positive tumors and 15 HER2-negative high-grade tumors by ISH. The histological examination indicated that patient samples could be divided into three major expression patterns: miR-21 predominantly in tumor stroma, predominantly in cancer cells, or in both stromal and cancer cells. There was no obvious difference between the HER2-positive and HER2-negative tumors in terms of the miR-21 expression patterns and intensities. To explore the possibility that miR-21 expression levels and/or cellular localization could predict resistance to adjuvant trastuzumab in HER2-positive breast cancer patients, we analyzed additional 16 HER2-positive tumors from patients who were treated with trastuzumab in the adjuvant setting. Eight of the 16 patients showed clinical recurrence and were considered resistant. Examination of the miR-21 expression patterns and intensities revealed no association between the miR-21 scores in the cancer cell population (p = 0.69) or the stromal cells population (p = 0.13) and recurrent disease after adjuvant trastuzumab. Thus, our findings show that elevated miR-21 expression does not predict resistance to adjuvant trastuzumab.

HER2-encoded mir-4728 forms a receptor-independent circuit with miR-21-5p through the non-canonical poly(A) polymerase PAPD5

“…Finally, to study if the mechanisms identified in these cell line experiments are also present in breast tumours we used samples included in the population-based breast cancer project SCAN-B 23 . This analysis may be complicated by the fact that miR-21-5p has a dynamic expression in different cell types within the tumour 24 while the tumour data represents bulk tumour RNA with varying percentages of cancer cells. We selected 186 breast tumour samples, produced small RNA sequencing data from the extracted total RNA and used poly(A)-positive mRNA-sequencing data to classify samples into the intrinsic subtypes according to the expression of genes included in the PAM50 classifier.…”

Effect of silibinin-loaded nano-niosomal coated with trimethyl chitosan on miRNAs expression in 2D and 3D models of T47D breast cancer cell line

“…MiR-15a is a member of the pro-apoptotic miRNA cluster and several studies have confirmed the decreased expression in breast cancer [41,42]. MiR-21 is an oncogene which is over-expressed and plays as an anti-apoptotic factor in most breast cancers [20,41,43]. MiR-200c and miR-141 are two members of the miR-200 family, which have been shown to function as tumour-suppressive miRNAs by targeting multiple oncogenic factors.…”

Small RNA Detection by in Situ Hybridization Methods

“…Multiplex analysis of different miRNAs enables distinguishing between different types of cancers [ 22 , 103 ]. Examples of specific miRNAs that show high changes in cancerous cells that were imaged with ISH methods are miR-21 in colon adenocarcinomas and gliomas as well as pancreatic and breast cancer [ 99 , 100 , 104 , 105 , 106 , 107 ], miR-10b in pancreatic ductal adenocarcinoma [ 108 ] and miR-221 in breast cancer [ 109 ].…”