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

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

doi:10.1038/srep41776

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

Sci Rep. 2017 Feb 2:7:41776. doi: 10.1038/srep41776.

Authors

Zheyong Liang^{1

2}, Wenjie Li^{1

2}, Jie Liu^{1

2}, Juan Li^{1

2}, Fang He¹, Yina Jiang³, Lu Yang¹, Pingping Li^{1

2}, Bo Wang^{1

2}, Yaochun Wang^{1

2}, Yu Ren⁴, Jin Yang⁵, Zhijun Luo⁶, Cyrus Vaziri⁷, Peijun Liu^{1

2}

Affiliations

¹ Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
² Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
³ Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
⁴ Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
⁵ Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
⁶ Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
⁷ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Hormonal / pharmacology
Apoptosis / drug effects
Biomarkers, Tumor
Breast Neoplasms / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
DNA Damage
DNA Replication / drug effects*
Disease Models, Animal
Drug Resistance, Neoplasm / drug effects*
Drug Synergism
Female
Gene Expression
Gene Knockdown Techniques
Histones / genetics
Histones / metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
Mice
Minichromosome Maintenance Complex Component 7 / antagonists & inhibitors*
Minichromosome Maintenance Complex Component 7 / genetics
Minichromosome Maintenance Complex Component 7 / metabolism
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism
Simvastatin / pharmacology*
Tamoxifen / pharmacology*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Hormonal
Biomarkers, Tumor
Histones
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Retinoblastoma Protein
Tamoxifen
Simvastatin
MCM7 protein, human
Minichromosome Maintenance Complex Component 7