Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo.
Triple-negative breast cancer (TNBC) is the most lethal form of breast cancer. Lacking effective therapeutic options hinders treatment of TNBC. Here, we show that bepridil (BPD) and trifluoperazine (TFP), which are FDA-approved drugs for treatment of schizophrenia and angina respectively, inhibit Akt-pS473 phosphorylation and promote FOXO3 nuclear localization and activation in TNBC cells. BPD and TFP inhibit survival and proliferation in TNBC cells and suppress the growth of TNBC tumors, whereas silencing FOXO3 reduces the BPD- and TFP-mediated suppression of survival in TNBC cells. While BPD and TFP decrease the expression of oncogenic c-Myc, KLF5, and dopamine receptor DRD2 in TNBC cells, silencing FOXO3 diminishes BPD- and TFP-mediated repression of the expression of these proteins in TNBC cells. Since c-Myc, KLF5, and DRD2 have been suggested to increase cancer stem cell-like populations in various tumors, reducing these proteins in response to BPD and TFP suggests a novel FOXO3-dependent mechanism underlying BPD- and TFP-induced apoptosis in TNBC cells.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.|Current address: Department of Biological and Chemical Engineering, Hongik University, Sejong, 339-701, Korea.
See-Hyoung
SH
Park
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Young Min
YM
Chung
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jessica
J
Ma
Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, USA.
Qin
Q
Yang
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Jonathan S
JS
Berek
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Mickey C-T
MC
Hu
D000818:Animals; D017209:Apoptosis; D015764:Bepridil / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism
C581293:DRD2 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D017448:Receptors, Dopamine D2; D014268:Trifluoperazine; D015764:Bepridil; D004298:Dopamine
FOXO3; bepridil; breast cancer; dopamine receptor; trifluoperazine