Abstract 3582: PPAR gamma acetylation governs mammary adenocarcinoma tumor growth via acetylated residues that determine DNA sequence-specific binding

Abstract

Abstract Background: HER2/neu overexpression in breast cancer confers a lipogenic phenotype. Although the introduction of anti-Her2 therapies has led to dramatic improvements in survival, nearly all patients with metastatic Her2-positive breast cancer will progress on treatment suggesting the importance of developing coextinction approaches targeting multiple pathways. Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. PPARγ binds additional DNA cis elements associated with other transcription factors, including C/EBPs, NFκB and AP-1 proteins, to promote non-canonical signaling. Defining the mechanisms governing the selection of canonical versus non-canonical PPARγ binding sequences may provide the opportunity to design regulators with distinct functions and side effects. PPARγ1 acetylation at K268/293 participates in the regulation of adipose tissue differentiation (1), and the conserved lysine residues (K154/155) govern lipogenesis in breast cancer cells (2). Although Cre based Pparγ1 gene deletion in mammary tumor oncomice showed Pparγ1 participates in the onset and progression of ErbB2-induced mammary tumorigenesis (3), the molecular mechanisms and the post-translational modifications of PPARγ governing Pparγ1 tumorigenic function remained to be determined. Methods: Herein, we defined the role of PPARγ1 acetylation in breast cancer growth in immune-deficient mice using distinct breast cancer cell lines (MCF10-Ras, MCF10A-NeuT). Furthermore, using ChIP and ChIP-Seq we show that the acetylated residues of Pparγ1 altered preference of cis-element binding in chromatin to augment Pparγ non-canonical binding. Results: Herein, the PPARγ1 acetylated residues K154/155 were shown to be essential for the induction of transcriptional modules governing growth factor signaling, cellular apoptosis, and autophagy in mice. The K154/155 residues determined the selection of genome-wide DNA binding sites, altering the selection from canonical to non-canonical (C/EBP) DNA sequence-specific binding. The gene signature reflecting the acetylation-dependent genomic occupancy provided predictive value in patient survival outcomes. Conclusions: Endogenous Pparγ1 promotes mammary tumor onset and progression. PPARγ1 breast tumor induction involves K154/155, which governs transcriptional programs (growth, apoptosis, and autophagy) via transcriptional complex binding to canonical vs. non-canonical regulatory elements. Pparγ1 acetylation participates in ErbB2-induced breast cancer tumor growth and inflammation and may represent a relevant target for therapeutic coextinction.