Quercetin Inhibits Lef1 and Resensitizes Docetaxel-Resistant Breast Cancer Cells.

Marta Prieto-Vila,Takahiro Ochiya,Akiko Kogure,Wataru Usuba,Ryou-U Takahashi,Yusuke Yamamoto,Iwao Shimomura

doi:10.3390/molecules25112576

Abstract

Drug resistance is a major problem for breast cancer patients. Docetaxel is an anti-mitotic agent that serves as first line of treatment in metastatic breast cancer, however it is susceptible to cellular drug resistance. Drug-resistant cells are able to spread during treatment, leading to treatment failure and eventually metastasis, which remains the main cause for cancer-associated death. In previous studies, we used single-cell technologies and identified a set of genes that exhibit increased expression in drug-resistant cells, and they are mainly regulated by Lef1. Furthermore, upregulating Lef1 in parental cells caused them to become drug resistant. Therefore, we hypothesized that inhibiting Lef1 could resensitize cells to docetaxel. Here, we confirmed that Lef1 inhibition, especially on treatment with the small molecule quercetin, decreased the expression of Lef1 and resensitized cells to docetaxel. Our results demonstrate that Lef1 inhibition also downregulated ABCG2, Vim, and Cav1 expression and equally decreased Smad-dependent TGF-β signaling pathway activation. Likewise, these two molecules worked in a synergetic manner, greatly reducing the viability of drug-resistant cells. Prior studies in phase I clinical trials have already shown that quercetin can be safely administered to patients. Therefore, the use of quercetin as an adjuvant treatment in addition to docetaxel for the treatment of breast cancer may be a promising therapeutic approach.

Highlights

Drug resistance to anticancer therapies is a major problem worldwide
Since Lymphoid enhancer-binding factor-1 (Lef1) overexpression induced an associated change in gene expression that eventually
Lef1 is a DNA-binding transcription factor that has a central role in the canonical Wnt

Summary

Introduction

Drug resistance to anticancer therapies is a major problem worldwide. Drug resistance leads to treatment failure and tumor recurrence and eventually to metastasis, which dramatically decreases the5-year survival rate of breast cancer patients despite a good initial prognosis [1]. Drug resistance to anticancer therapies is a major problem worldwide. Drug resistance leads to treatment failure and tumor recurrence and eventually to metastasis, which dramatically decreases the. 5-year survival rate of breast cancer patients despite a good initial prognosis [1]. Its use has been associated with a statistically significant reduction in mortality; it is susceptible to cellular drug resistance caused, for instance by drug efflux-associated proteins [2]. We used single-cell technology and performed in depth analysis on the dynamic alterations of the transcriptome in a luminal subtype of breast cancer cells, MCF7 cells, throughout the acquisition of drug resistance to DTX [3]. We elucidated a set of genes responsible for drug resistance. The identified drug-resistant gene profile included an Molecules 2020, 25, 2576; doi:10.3390/molecules25112576 www.mdpi.com/journal/molecules

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Conclusion