Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers
Journal
Cell Death Discovery
Journal Volume
7
Journal Issue
1
Date Issued
2021-12-01
Author(s)
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
Hui, Kam Man
Wang, Lingzhi
Goh, Boon Cher
Kumar, Alan Prem
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.
Subjects
MANGANESE SUPEROXIDE-DISMUTASE; LIGAND TROGLITAZONE; MULTIPLE-MYELOMA; COLON-CANCER; PHASE-II; IN-VITRO; THERAPY; RECEPTOR; EXPRESSION; CARCINOMA
SDGs
Publisher
SPRINGERNATURE
Type
journal article