KIF11 is required for proliferation and self-renewal of docetaxel resistant triple negative breast cancer cells.

Meng Jiang,Junzhe Ma,Yuantao Wu,Zhixiang Zhuang,Rui Xia,Huiru Zhuang,Lei Gan,Yihui Sun

doi:10.18632/oncotarget.20785

Meng Jiang, Junzhe Ma + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.20785

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Abstract

Development of chemoresistance remains a major hurdle for triple negative breast cancer treatment. Previous studies suggest that CD44+/CD24- cells, subpopulation of cancer stem cells with self-renewing and tumor-initiating capacities, are partly responsible for chemoresistance and therapeutic failure of triple negative breast cancer. Therefore, novel agents that target cancer stem cells (CSCs) may improve the clinical outcome. KIF11 (kinesin family member 11), overexpressed in many cancer cells, is a molecular motor protein that plays essential role in mitosis. In this study, we assess its role in docetaxel resistant triple negative breast cancer (TNBC). We found that the expression of KIF11 was significantly increased in CD44+/CD24- subpopulation of docetaxel resistant TNBC cells. Knockdown of KIF11 resulted in a significant decrease in the percentage of CSCs and mammosphere formation. KIF11 knockdown also inhibits cell growth and induces cell cycle G2/M arrest followed by cell mitosis and apoptosis. Further docetaxel resistant TNBC xenograft models demonstrated that KIF11 inhibitor exerts growth inhibitory effect in vivo. Of note, we also found that KIF11 was highly expressed in TNBC and its expression was correlated with shorter disease free survival time. All these data indicate that KIF11 is critical for proliferation and self-renewal in TNBC tumor cells in vitro and in vivo, suggesting that KIF11 may be a promising therapeutic target for treating chemoresistant TNBC.

Highlights

Breast cancer is a highly heterogeneous malignancy that has become one of the leading causes of cancerrelated death for women worldwide [1]
Consistent with the previous study, CD44+/CD24- phenotype percentage was significantly higher in the docetaxel resistant triple negative breast cancer (TNBC) cells than their paternal TNBC cells (Figure 1A)
We analyzed the expression of KIF11 in the docetaxel resistant TNBC cell lines and their paternal cell lines in order to investigate whether KIF11 was involved in TNBC docetaxel resistance

Summary

Introduction

Breast cancer is a highly heterogeneous malignancy that has become one of the leading causes of cancerrelated death for women worldwide [1]. Triple negative breast cancer (TNBC), characterized by the lack expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for approximately 15 to 20%. Docetaxel, which polymerizes tubulin to disrupt normal microtubule dynamics leading to cell death, is one of the most common chemotherapies for TNBC. Chemoresistance remains a major hurdle for the docetaxel based chemotherapy. Analysis of human tumor tissues has provided evidence of a small population of stem-like cells that have been labeled as cancer stem cells (CSC). This population is able to dictate invasion, metastasis, and therapeutic resistance in tumors. Breast cancer stem-like cell (BCSC) populations have been identified based on the cell membrane marker CD44+/CD24- [7].

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