Essential roles of noncanonical signaling of JAK1 and JAK2 in mammary gland development and breast cancer

The postnatal development of the mammary gland is dependent on a multitude of cellular programs that are orchestrated by steroid and peptide hormones as well as locally produced cytokines. Two Janus kinases, JAK1 and JAK2, are obligatory intracellular signaling mediators of many peptide hormones and cytokines that have essential functions for the growth, differentiation, and survival of the mammary epithelium. Previous work from several laboratories including our own has established that JAK1 and JAK2 have non-redundant functions for the activation of specific Signal Transducers and Activators of Transcription (STATs) in normal and neoplastic epithelial cells. Important roles of these canonical JAK/STAT signaling cascades during mammogenesis are generally thought to be limited to the differentiation and remodeling of alveolar cells during the gestation cycle. In contrast to this notion, our team has discovered that JAK1 and JAK2 synergistically control the postnatal development of the mammary epithelial ductal tree. We uncovered that STAT proteins are activated in a compensatory manner in ductal epithelial cells, but the collective results from several genetically engineered mouse models revealed that the cooperative functions of JAK1 and JAK2 are not facilitated by their downstream STATs. Unlike in JAK1/2 mammary-specific double knockout mice, the growth and survival of mammary epithelial cells do not require the expression and/or activation of the seven known mammalian STAT proteins. We, therefore, propose that the biologically relevant functions of JAKs during postnatal mammary gland development are facilitated by noncanonical molecular signaling mechanisms of JAK1 and JAK2. Additional preliminary findings also raise the issue of whether the significant biological roles of JAKs are solely dependent on the functionality of their tyrosine kinase domains. To interrogate the noncanonical functions of JAK signaling, we will first establish whether the JAK1/2-dependent signaling mechanisms that govern the development of a mammary gland are dependent on the kinase and/or scaffold functions of JAKs (aim 1). Next, we will investigate the activation of JAK substrates that are currently known and use state-of-the-art genomic and proteomic approaches to identify novel targets and pathways that rely on JAK1 and JAK2 without the expression and activation of STATs (aim 2). Since JAK1/2 kinase inhibitors were clinically ineffective in treating advanced breast cancers, we will investigate the significance of noncanonical JAK signaling in mammary tumor cells and the effects of pharmacologically targeting JAK1/2 for degradation in human-relevant breast cancer models (aim 3). The collective outcomes of this project are expected to provide substantial new insights into the central roles of peptide hormone and cytokine signaling in mammary gland development. The anticipated results from the three aims will elucidate novel molecular mechanisms by which Janus kinases signal within normal and neoplastic epithelial cells beyond the activation of STAT proteins and establish whether pharmacologically targeting JAK1/2 for degradation is a suitable strategy for the treatment of breast cancer. Project Number: 1R01CA307125-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Kay-Uwe Wagner | Institution: WAYNE STATE UNIVERSITY, DETROIT, MI | Award Amount: $371,024 | Activity Code: R01 | Study Section: Integrative and Clinical Endocrinology and Reproduction Study Section[ICER] View on NIH RePORTER: https://reporter.nih.gov/project-details/11268582