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.
Highlights
Breast cancers—the leading cause of cancer-related deaths among women—encompass a diverse and heterogeneous group of disease entities [1]
We demonstrated that nature of which is in keeping with the better-known function of relieving these repressive circuitries with clinically approved or HDAC1/2 to modulate gene transcription through modifying experimental histone deacetylase (HDAC) inhibitors is essential to convert peroxisome proliferatoractivated receptor-γ (PPARγ) into a chromatin accessibility
Since the quintessential proangioited significantly higher HDAC1 and HDAC2 expression compared to other subtypes (P = 4.9 × 10−19 and P = 4.5 × 10−156, respecgenic growth factor, VEGF-A was delineated through systems biology and reverse transcription (RT)-qPCR to be downregulated in a greater-than-additive manner tively), while luminal A and luminal B cases featured higher by combination treatment, we extended our investigations to
Summary
Breast cancers—the leading cause of cancer-related deaths among women—encompass a diverse and heterogeneous group of disease entities [1]. Ligand activation of PPARγ has been found to exert anti-tumor effects in diverse preclinical models including breast cancer by inducing apoptosis, differentiation, cell growth inhibition and cell cycle arrest [3,4,5,6,7,8,9]. The notion that PPARγ could function as a tumor suppressor was reinforced by large epidemiological studies which observed that diabetic patients receiving thiazolidinediones had up to ~33% lowered risk for developing certain malignancies [10, 11]. These observations galvanized a few small clinical trials to examine the Edited by Dr Ivano Amelio
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