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 <i>Ppar</i><i>γ</i><i>1</i> restrained mammary tumor progression, lipogenesis, and induced local mammary tumor macrophage infiltration, without affecting other tissue hematopoietic stem cell pools. Endogenous <i>Ppar</i><i>γ</i><i>1</i> induced expression of both an EphA2-Amphiregulin and an inflammatory INFγ and Cxcl5 signaling module, that was recapitulated in human breast cancer. <i>Ppar</i><i>γ</i><i>1</i> bound directly to growth promoting and proinflammatory target genes in the context of chromatin. We conclude <i>Ppar</i><i>γ</i><i>1</i> promotes ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Herein, endogenous <i>Ppar</i><i>γ</i><i>1</i> 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 <i>Ppar</i><i>γ</i><i>1</i> may provide the rationale for complementary coextinction programs in ErbB2 tumors.

Keywords: breast cancer; lipogenesis; peroxisome proliferator-activated receptor gamma (PPARγ), nuclear receptor.