Ppar Gamma 1 Facilitates Erbb2-Mammary Adenocarcinoma In Mice

Simple Summary: HER2, which is associated with clinically aggressive disease, is overexpressed in 15-20% of breast cancers (BC). Peroxisome proliferator-activated receptor gamma (PPAR gamma), is expressed in a variety of malignancies. The aim of our study was to determine the function of endogenous Ppar gamma 1 in the onset and progression of mammary tumors induced by ErbB2 in mice. Genetic deletion of Ppar gamma 1 slowed the rate of tumor progression and death from ErbB2-induced mammary tumors. The deletion of Ppar gamma 1 correlated with reduced pro-tumorigenic inflammation. We conclude ErbB2 collaborates with endogenous Ppar gamma 1 in the onset and progression of mammary tumorigenesis.HER2, which is associated with clinically aggressive disease, is overexpressed in 15-20% of breast cancers (BC). The host immune system participates in the therapeutic response of HER2(+) breast cancer. Identifying genetic programs that participate in ErbB2-induced tumors may provide the rational basis for co-extinction therapeutic approaches. Peroxisome proliferator-activated receptor gamma (PPAR gamma), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Herein, genetic deletion of endogenous Ppar gamma 1 restrained mammary tumor progression, lipogenesis, and induced local mammary tumor macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Endogenous Ppar gamma 1 induced expression of both an EphA2-Amphiregulin and an inflammatory INF gamma and Cxcl5 signaling module, that was recapitulated in human breast cancer. Ppar gamma 1 bound directly to growth promoting and proinflammatory target genes in the context of chromatin. We conclude Ppar gamma 1 promotes ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Herein, endogenous Ppar gamma 1 promoted ErbB2-mediated mammary tumor onset and progression. PPAR gamma 1 increased expression of an EGF-EphA2 receptor tyrosine kinase module and a cytokine/chemokine 1 transcriptional module. The induction of a pro-tumorigenic inflammatory state by Ppar gamma 1 may provide the rationale for complementary coextinction programs in ErbB2 tumors.