Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression

Abstract

Summary: Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a breast cancer model that conditionally lacks Janus kinase 1, we show here that JAK1 is essential for IL-6-class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling, which promotes tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6-class cytokines, which are master regulators of cancer-associated inflammation. : Wehde et al. demonstrate that JAK1 is the pivotal kinase that controls cytokine-mediated activation of three STAT proteins in ERBB2-driven mammary cancer cells. They provide experimental evidence that deficiency in JAK1/STAT3 signaling and consequential downregulation of oncogenic targets inhibit migration, tumorsphere formation, and metastatic dissemination of mammary cancer cells. Keywords: breast cancer, mammary neoplasms, Janus kinase 1, Stat transcription factor, gene targeting, signal transduction, Cre recombinase, RNA sequencing, c-Fos, MAP3K8