Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41420-021-00635-5
Title: Epigenetic derepression converts PPAR gamma into a druggable target in triple-negative and endocrine-resistant breast cancers
Authors: Loo, Ser Yue
Syn, Nicholas L
Koh, Angele Pei-Fern 
Teng, Janet Cheng-Fei 
Deivasigamani, Amudha
Tan, Tuan Zea 
Thike, Aye Aye 
Vali, Shireen 
Kapoor, Shweta
Wang, Xiaoyuan 
Wang, Jiong Wei 
Tan, Puay Hoon 
Yip, George W 
Sethi, Gautam 
Huang, Ruby Yun-Ju 
Hui, Kam Man 
Wang, Lingzhi 
Goh, Boon Cher 
Kumar, Alan Prem 
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
MANGANESE SUPEROXIDE-DISMUTASE
LIGAND TROGLITAZONE
MULTIPLE-MYELOMA
COLON-CANCER
PHASE-II
IN-VITRO
THERAPY
RECEPTOR
EXPRESSION
CARCINOMA
Issue Date: 27-Sep-2021
Publisher: SPRINGERNATURE
Citation: Loo, Ser Yue, Syn, Nicholas L, Koh, Angele Pei-Fern, Teng, Janet Cheng-Fei, Deivasigamani, Amudha, Tan, Tuan Zea, Thike, Aye Aye, Vali, Shireen, Kapoor, Shweta, Wang, Xiaoyuan, Wang, Jiong Wei, Tan, Puay Hoon, Yip, George W, Sethi, Gautam, Huang, Ruby Yun-Ju, Hui, Kam Man, Wang, Lingzhi, Goh, Boon Cher, Kumar, Alan Prem (2021-09-27). Epigenetic derepression converts PPAR gamma into a druggable target in triple-negative and endocrine-resistant breast cancers. CELL DEATH DISCOVERY 7 (1). ScholarBank@NUS Repository. https://doi.org/10.1038/s41420-021-00635-5
Abstract: Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.
Source Title: CELL DEATH DISCOVERY
URI: https://scholarbank.nus.edu.sg/handle/10635/208376
ISSN: 20587716
DOI: 10.1038/s41420-021-00635-5
Appears in Collections:Staff Publications
Elements

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers.pdf5.09 MBAdobe PDF

OPEN

NoneView/Download

Page view(s)

57
checked on May 12, 2022

Download(s)

1
checked on May 12, 2022

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.