Details

Autor(en) / Beteiligte

• 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

Titel

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

Ist Teil von

• Cell death discovery, 2021-09, Vol.7 (1), p.265-265, Article 265

Ort / Verlag

New York: Springer Nature B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.