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

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.

• Authors: 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
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 41776 (02 02 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28150753 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, metabolism)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Mice
• Minichromosome Maintenance Complex Component 7 (antagonists & inhibitors, genetics, metabolism)
• Retinoblastoma Protein (genetics, metabolism)
• Simvastatin (pharmacology)
• Tamoxifen (pharmacology)
• Xenograft Model Antitumor Assays