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

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.

Integrated network pharmacology and experimental verification to explore the potential mechanism of San Ying decoction for treating triple-negative breast cancer

“…VSP-17, an agonist of PPARγ, inhibits the migration and invasion of TNBC cells by inhibiting the EMT process [28] . In patients with breast cancer, PPARγ expression has a significant beneficial effect on recurrence-free survival [29] . Similarly, PPARγ level is lower in patients with local recurrence than in those who are disease free.…”

Asiaticoside hampers epithelial–mesenchymal transition by promoting PPARG expression and suppressing P2RX7‐mediated TGF‐β/Smad signaling in triple‐negative breast cancer

“…PPARG was found to be the one with a significant correlation with metastasis‐free survival of patients with TNBC among the 12 hub factors we screened out. Regulatory networks orchestrated by PPARG control pleiotropic cellular processes related to angiogenesis, cell cycle, and proliferation (Loo et al, 2021). Consistently, VSP‐17, a PPARG agonist, suppressed the liver metastasis of TNBC by enhancing the expression of E‐cadherin (Y. Wang et al, 2018).…”

HDAC Inhibitors Enhance Efficacy of the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T in Pancreatic and Triple-Negative Breast Cancer Models

“…Epigenetic alterations also play important roles in cancer development and progression, with specific epigenetic profiles dependent on tumour type. For example, HDAC enzymes from Class I (HDAC1, 2, 3 and 8) have been reported to be overexpressed in breast cancer [ 22 , 23 ]. HDAC2 and 3 are frequently expressed at high levels in hormone-receptor negative tumours, while aberrant HDAC1 expression is common in hormone-receptor positive tumours.…”