Breast cancer (BC) is the second leading cause of cancer related deaths among women in the US. While advances in treatment and early detection have contributed to a decline in death rates, BC is still a major killer of women both in the US and globally highlighting the need to identify new molecular circuits and treatment strategies to combat this disease. Work from our funded Merit studies and others has shown that the RON receptor tyrosine kinase is highly overexpressed in human BCs and is an independent predictor of worse overall survival, early death and metastatic progression. Interestingly, our recent studies show that RON expression is independent of molecular subtype suggesting that this protein may serve as a powerful new marker for metastasis, poor prognosis and recurrence across all BCs. While RON overexpression is a decisive factor in human BC progression, our knowledge about the mechanisms by which RON promotes the development of aggressive disease is limited. Previously, our laboratory produced transgenic mice with mammary-specific RON overexpression. These mice, referred to as MMTV-RON mice, mimic the aggressive disease pattern observed in human patients with all female mice developing highly metastatic breast tumors. In this clinically relevant model, we discovered that mammary tumors upregulate the RON ligand, hepatocyte growth factor-like protein (HGFL). Utilizing MMTV-RON mice deficient in HGFL, we published the requirement of HGFL for oncogenic RON activation and mammary tumor growth and progression. Utilizing HGFL deficient BC cells, we showed that reconstitution of HGFL promoted tumor cell autonomous survival, migration and invasion. Further, we showed that global HGFL loss also reduced breast cancer stem-like cell numbers and altered the tumor microenvironment (TME) by regulating immune cell recruitment, macrophage polarization, and cytotoxic T cell responses. In complementary studies using the well-characterized polyomavirus middle T antigen mouse model of BC, we show that RON loss specifically in mammary epithelial cells phenocopies the reduced growth, metastasis and changes in the TME as global and tumor cell specific HGFL loss. We also demonstrate a coordinate upregulation of HGFL and RON in human BCs. To gain mechanistic insights into the RON signaling pathway, we performed RNA-Seq analyses of RON modulated human and murine BC cells. Surprisingly, we found RON predominately suppressed pathways involved in Type I interferon (IFN), cytokine and pattern recognition receptor (PRR) signaling. Investigating these pathways, we discovered a novel connection between RON and suppression of IRAK4 (interleukin-1 receptor-associated kinase 4), an identified mediator of innate immune responses downstream of PRRs. We also identified a reduction in IRF7, a key regulator of Type I IFNs, with RON loss and IRAK4 expression. We show that IRAK4 introduction into RON expressing cells phenocopies RON loss, while treatment of RON deficient ce...