Abstract PS17-58: Pparg1 induces an EGF-EphA2 receptor tyrosine kinase module to promote ErbB2- mammary adenocarcinoma in mice

ErbB2 is overexpressed in approximately 25% of human breast cancers, associated with clinically aggressive disease. No soluble ligand has been identified and the receptor is regulated by heterodimerization with other ErbB family receptors, including EGFR, and other receptor tyrosine kinases including EphA2. EGFR is activated by seven different growth factors including EGF and Amphiregulin. Downstream signaling modules required for ErbB2 induced tumorigenesis in genetically engineered mouse models (GEMM) include the phosphatidylinositol 3-kinase/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway and the phospholipase C (PLCγ) pathways. ErbB2-mediated tumorigenesis involves activation of receptor tyrosine kinases, induction of cyclin D1/CDK activity, and functional restraint by tumor suppressors. The receptor tyrosine kinase EPH receptor A2 (EphA2), a member of the Eph RTK family, is overexpressed in aggressive breast cancer and EphA2 forms a complex with ErbB2 thereby enhancing ErbB2-induced tumor onset and progression. The host immune system participates in the therapeutic response of HER2+ breast cancer. The tumor microenvironment (TME) is regulated by chemokines and their G protein coupled receptors binds several ligands, including Cxcl5 which binds Cxcr2, to augment the pro-tumor immune response, tumor growth and metastasis. Identifying genetic programs that participate in ErbB2-induced tumors may provide the rational basis for co-extinction therapeutic approaches. Peroxisome proliferator-activated receptor γ (PPARγ), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Herein, genetic deletion of endogenous Pparγ1 restrained mammary tumor progression, lipogenesis, and induced local mammary tumor F4/80+ tumor-associated macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Pparγ1 induced peroxisomal target genes in the mammary tumors as evidenced by increased expression of PEX-11, together with PPARGC1 and ESRR induced regulator, muscle 1, Perm1 (PGC-1 and ERR-induced Regulator in Muscle 1). Peroxisomes induced by Pparγ1, activated Type1 interferons (IFNs) and IFN-stimulated gene expression, including Cxcl5. Endogenous Pparγ1 induced expression of both an EphA2-Amphiregulin and an inflammatory INFγ -Cxcl5 signaling module. Pparγ1 bound directly to growth promoting and proinflammatory target genes in the context of chromatin. We conclude Pparγ1 promotes ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Citation Format: Richard G Pestell, Xuanmao Jiao, Andrew V Kossenkov, Adam Ertel, Wei Tong, Zhao Zhang, Peter A McCue. Pparg1 induces an EGF-EphA2 receptor tyrosine kinase module to promote ErbB2- mammary adenocarcinoma in mice [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-58.