Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo

• Published in: Oncotarget Vol. 7; no. 27; pp. 42110 - 42125
• Main Authors: Park, See-Hyoung, Chung, Young Min, Ma, Jessica, Yang, Qin, Berek, Jonathan S, Hu, Mickey C-T
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 05.07.2016
• Subjects: Animals; Apoptosis; Bepridil - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Nucleus - metabolism; Dopamine - metabolism; Female; Forkhead Box Protein O3 - metabolism; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Kruppel-Like Transcription Factors - metabolism; MCF-7 Cells; Mice; Mice, Nude; Neoplastic Stem Cells; Phosphorylation; Proto-Oncogene Proteins c-myc - metabolism; Receptors, Dopamine D2 - metabolism; Research Paper; RNA, Small Interfering - metabolism; Trifluoperazine - pharmacology; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; breast cancer; trifluoperazine; FOXO3; bepridil; dopamine receptor
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9881

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.