Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency.
We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4.
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea.
Hae Hyun
HH
Jung
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Soo-Hyeon
SH
Lee
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Ji-Yeon
JY
Kim
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Jin Seok
JS
Ahn
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea.|Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.|Biomedical Research Institute, Samsung Medical Center, Seoul 06351, Korea.
Yeon Hee
YH
Park
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.|Biomedical Research Institute, Samsung Medical Center, Seoul 06351, Korea.
Young-Hyuck
YH
Im
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002867:Chromones / Q000494:pharmacology; D054637:Dual-Specificity Phosphatases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D002070:Butadienes; D002867:Chromones; C494041:ETS1 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C000715470:MAS1 protein, human; D009025:Morpholines; D009570:Nitriles; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D000090063:Proto-Oncogene Mas; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D014157:Transcription Factors; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019821:Simvastatin; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases