Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells.
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.
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Zheyong
Z
Liang
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Wenjie
W
Li
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Jie
J
Liu
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Juan
J
Li
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Fang
F
He
Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
Yina
Y
Jiang
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Lu
L
Yang
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Pingping
P
Li
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Bo
B
Wang
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Yaochun
Y
Wang
Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
Yu
Y
Ren
Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
Jin
J
Yang
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
Zhijun
Z
Luo
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Cyrus
C
Vaziri
Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.|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.
Peijun
P
Liu
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D064168:Minichromosome Maintenance Complex Component 7 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D006657:Histones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016160:Retinoblastoma Protein; D013629:Tamoxifen; D019821:Simvastatin; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7