Pparγ1 Facilitates ErbB2-Mammary Adenocarcinoma in Mice.

Abstract

Simple SummaryHER2, which is associated with clinically aggressive disease, is overexpressed in 15–20% of breast cancers (BC). Peroxisome proliferator-activated receptor γ (PPARγ), is expressed in a variety of malignancies. The aim of our study was to determine the function of endogenous Pparγ1 in the onset and progression of mammary tumors induced by ErbB2 in mice. Genetic deletion of Pparγ1 slowed the rate of tumor progression and death from ErbB2-induced mammary tumors. The deletion of Pparγ1 correlated with reduced pro-tumorigenic inflammation. We conclude ErbB2 collaborates with endogenous Pparγ1 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 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 macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Endogenous Pparγ1 induced expression of both an EphA2-Amphiregulin and an inflammatory INFγ and Cxcl5 signaling module, that was recapitulated in human breast cancer. 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. Herein, endogenous Pparγ1 promoted ErbB2-mediated mammary tumor onset and progression. PPARγ1 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 Pparγ1 may provide the rationale for complementary coextinction programs in ErbB2 tumors.