Loo, Ser YueSer YueLooSyn, Nicholas L.Nicholas L.SynKoh, Angele Pei FernAngele Pei FernKohTeng, Janet Cheng FeiJanet Cheng FeiTengDeivasigamani, AmudhaAmudhaDeivasigamaniTan, Tuan ZeaTuan ZeaTanThike, Aye AyeAye AyeThikeVali, ShireenShireenValiKapoor, ShwetaShwetaKapoorWang, XiaoyuanXiaoyuanWangWang, Jiong WeiJiong WeiWangTan, Puay HoonPuay HoonTanYip, George W.George W.YipSethi, GautamGautamSethiRUBY YUN-JU HUANGHui, Kam ManKam ManHuiWang, LingzhiLingzhiWangGoh, Boon CherBoon CherGohKumar, Alan PremAlan PremKumar2023-01-162023-01-162021-12-012058-7716https://scholars.lib.ntu.edu.tw/handle/123456789/627262Clinical 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.enMANGANESE SUPEROXIDE-DISMUTASE; LIGAND TROGLITAZONE; MULTIPLE-MYELOMA; COLON-CANCER; PHASE-II; IN-VITRO; THERAPY; RECEPTOR; EXPRESSION; CARCINOMA[SDGs]SDG3journal article10.1038/s41420-021-00635-5345802862-s2.0-85115775359WOS:000700398400001https://api.elsevier.com/content/abstract/scopus_id/85115775359