@article{5fb5cdb1ec93410fa29de955558edd8c,
title = "Identification of bbox1 as a therapeutic target in triple-negative breast cancer",
abstract = "Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG–dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degrada-tion. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1-mediated glycolysis, which leads to apoptosis and impaired cell-cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacologic inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting the previously uncharacter-ized BBOX1–IP3R3–calcium oncogenic signaling axis in TNBC. SIGNIFICANCE: We provide evidence from unbiased screens that BBOX1 is a potential therapeutic target in TNBC and that genetic knockdown or pharmacologic inhibition of BBOX1 leads to decreased TNBC cell fitness. This study lays the foundation for developing effective BBOX1 inhibitors for treatment of this lethal disease.",
author = "Chengheng Liao and Yang Zhang and Cheng Fan and Herring, {Laura E.} and Juan Liu and Locasale, {Jason W.} and Mamoru Takada and Jin Zhou and Giada Zurlo and Lianxin Hu and Simon, {Jeremy M.} and Ptacek, {Travis S.} and Andrianov, {Victor G.} and Einars Loza and Yan Peng and Huanghe Yang and Perou, {Charles M.} and Qing Zhang",
note = "Funding Information: This work was supported by the Cancer Prevention and Research Institute of Texas (to Q. Zhang, CPRIT, RR190058), American Cancer Society (to Q. Zhang, RSG-18-059-01-TBE), NCI Breast SPORE program (to C.M. Perou, P50-CA58223), NCI (to C.M. Perou, R01-CA148761), and BCRF (to C.M. Perou). We thank all members of the Zhang, Perou, and Yang laboratories for helpful discussions and suggestions. We thank Dr. Ralph DeBerardinis and Children{\textquoteright}s Research Institute{\textquoteright}s Metabo-lomics Facility at UTSW for their help. We thank Dr. Shafi Kuchay and Dr. Michele Pagano for providing the IP3R3-mutant plasmids. We thank Dr. Osvalds Pugovics for help with BBOX1 inhibitors. We thank Yongjuan Xia, Stephanie Cohen, and Nana Nikolaishvili-Feinberg in the UNC Translational Pathology Laboratory for the IHC staining and data analysis. We thank Charlene Santos and colleagues in the UNC Animal Studies Core for help with animal studies. This research is based in part upon work conducted using the UNC Proteomics Core Facility, which is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = nov,
doi = "10.1158/2159-8290.CD-20-0288",
language = "English (US)",
volume = "10",
pages = "1707--1721",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "11",
}