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- Title
Epigenetic derepression converts PPARγ 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
- 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.
- Publication
Cell Death Discovery, 2021, Vol 7, Issue 1, p1
- ISSN
2058-7716
- Publication type
Article
- DOI
10.1038/s41420-021-00635-5