Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells

Zheyong Liang,Jie Liu,Wenjie Li,Yina Jiang,Peijun Liu,Yu Ren,Jin Yang,Cyrus Vaziri,Juan Li,Lu Yang,Bo Wang,Zhijun Luo,Fang He,Yaochun Wang,Pingping Li

doi:10.1038/srep41776

Abstract

Acquired tamoxifen resistance (TamR) remains a major challenge in breast cancer endocrine therapy. The mechanism of acquiring tamoxifen resistance remains elusive, and no effective drugs are available. In this investigation, we determined that the expression of the DNA damage marker γH2AX is upregulated under minichromosome maintenance protein 7 (MCM7) knockdown in phospho Ser807/811-retinoblastoma protein (p-Rb) defect cells. In addition, the expression of p-Rb was lower in TamR cells than in parental cells, and the expression of γH2AX was significantly upregulated when MCM7 was knocked down in TamR cells. Simvastatin, an agent for hypercholesterolemia treatment, activated the MCM7/p-RB/γH2AX axis and induced DNA damage in TamR cells, especially when combined with tamoxifen. Finally, in vitro and in vivo experiments demonstrated that simvastatin combined with tamoxifen increased TamR cell apoptosis and inhibited xenograft growth. In conclusion, simvastatin may suppress TamR cell growth by inhibiting MCM7 and Rb and subsequently inducing DNA damage.

Highlights

Adjuvant endocrine therapies can halve the recurrence rate of estrogen receptor (ER)-positive breast cancer
We previously showed that simvastatin, an agent for the treatment of hypercholesterolemia[16,17], reduces the expression of Minichromosome maintenance protein 7 (MCM7) and causes a significant upregulation of γH2AX expression; we proposed that simvastatin may cause DNA damage in tamoxifen-resistant breast cancer cells in which p-retinoblastoma protein (Rb) expression is low via downregulation of MCM7
These results indicate that our tamoxifen resistance (TamR) cell line models share some characteristics of mesenchymal-like human breast cancer stem cells (CSCs)[18]

Summary

Introduction

Adjuvant endocrine therapies can halve the recurrence rate of estrogen receptor (ER)-positive breast cancer. A selective estrogen receptor (ER) modulator, is most frequently used as an adjuvant endocrine therapy for women with ER-positive breast cancer[4,5]. Rb is a well-known G1/S checkpoint control protein[10,11], but the association of Rb defect with the potential dysregulated DNA replication in tamoxifen-resistant breast cancer cells has not been established. We hypothesized that under the dysregulated DNA replication conditions caused by the Rb defect in tamoxifen-resistant cells, the additional destruction of the MCM complex may cause severe DNA damage. We previously showed that simvastatin, an agent for the treatment of hypercholesterolemia[16,17], reduces the expression of MCM7 and causes a significant upregulation of γH2AX expression; we proposed that simvastatin may cause DNA damage in tamoxifen-resistant breast cancer cells in which p-Rb expression is low via downregulation of MCM7

Methods

Results

Conclusion