MicroRNA-101 inhibits cell progression and increases paclitaxel sensitivity by suppressing MCL-1 expression in human triple-negative breast cancer.

Xiaoping Liu,Xiaoti Lin,Lu Yang,Xinhua Xie,Cailu Song,Peng Liu,Hailin Tang,Jianping Chen,Xiaoming Xie,Neng Wang

doi:10.18632/oncotarget.4039

Xiaoping Liu, Xiaoti Lin + Show 8 more

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https://doi.org/10.18632/oncotarget.4039

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Abstract

Triple-negative breast cancer is the most aggressive breast cancer subtype. The aim of our study was to investigate the functional role of both miR-101 and MCL-1 in the sensitivity of human triple-negative breast cancer (TNBC) to paclitaxel. We found that the expression of miR-101 was strongly decreased in triple-negative breast cancer tissues and cell lines. The expression of miR-101 was not associated with clinical stage or lymph node infiltration in TNBC. Ectopic overexpression of miR-101 inhibit growth and induced apoptosis in vitro and suppressed tumorigenicity in vivo. MCL-1 was significantly overexpressed in most of the TNBC tissues and cell lines. Luciferase assay results confirmed MCL-1 as a direct target gene of miR-101. MiR-101 inhibited MCL-1 expression in TNBC cells and transplanted tumors. There was a negative correlation between the level of expression of miR-101 and MCL-1 in TNBC tissues. Suppression of MCL-1 enhanced the sensitivity of MDA-MB-435 cells to paclitaxel. Furthermore, miR-101 increased paclitaxel sensitivity by inhibiting MCL-1 expression. Our findings provide significant insight into the molecular mechanisms of TNBC carcinogenesis and may have clinical relevance for the development of novel, targeted therapies for TNBC.

Highlights

Breast cancer, the most common malignancy in women, is a heterogeneous disease with substantial diversity in histological and molecular characteristics that require specialized therapeutic interventions [1]
The miR-101 expression was decreased in seven of the eight breast cancer cell lines (BT-483, T47D, MCF7, SKBR3, BT-474, MDA-MB-435, MDA-MB-231, and MDA-MB-468) compared to the normal human mammary epithelial cell line MCF-10A (Figure 1A). These results indicated that miR-101 had lower expression in basallike cell lines compared to luminal cell lines. quantitative real-time PCR (qRT-PCR) revealed a decrease in miR-101 expression in 16 of 22 triple-negative breast cancer (TNBC) samples (72.7%) (Figure 1B)
While it has been reported previously that suppression of miR-101 leads to the overexpression of Myeloid cell leukemia 1 (MCL-1) in hepatocellular carcinoma and non-small-cell lung cancer [18, 22], the relationship between MCL-1 and miR-101 and their biological relevance in breast cancer have not yet been fully determined, especially in TNBC

Summary

Introduction

The most common malignancy in women, is a heterogeneous disease with substantial diversity in histological and molecular characteristics that require specialized therapeutic interventions [1]. The estrogen receptor (ER), the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) are the molecular biomarkers currently used in routine clinical practice to help make treatment decisions for breast cancer [3]. Current treatment modalities for TNBC are limited to surgery, radiation, and systemic chemotherapy due to the lack of more specific therapeutic targets. Patients often experience early relapse from distant tumor metastasis even if they initially respond well to the treatments. Over the past few decades, tremendous effort has been expended in the search for a molecular targeted therapy for TNBC with limited success [5]

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