Oncotarget

Research Papers:

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

See-Hyoung Park, Young Min Chung, Jessica Ma, Qin Yang, Jonathan S. Berek and Mickey C-T. Hu _

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Oncotarget. 2016; 7:42110-42125. https://doi.org/10.18632/oncotarget.9881

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Abstract

See-Hyoung Park1,2,*, Young Min Chung1,*, Jessica Ma1, Qin Yang3, Jonathan S. Berek1, Mickey C-T. Hu1

1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA

2Current address: Department of Biological and Chemical Engineering, Hongik University, Sejong, 339-701, Korea

3Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, USA

*These authors contributed equally to this work

Correspondence to:

Mickey C-T. Hu, email: [email protected]

Keywords: FOXO3, breast cancer, bepridil, trifluoperazine, dopamine receptor

Received: January 18, 2016     Accepted: May 12, 2016     Published: June 07, 2016

ABSTRACT

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.


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