Graduation Date

Fall 12-15-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Kay Wagner

Abstract

The development of the postnatal mammary gland is tightly controlled by peptide hormones and cytokines. The signaling of these extracellular ligands through their corresponding receptors rely on Janus Kinases (JAKs) that activate downstream Signal Transducers and Activators of Transcription (STATs). The JAK/STAT signaling pathway is crucial for processes such as growth, proliferation, and cell survival of the epithelial tissue, but also for the breakdown and remodeling of the mammary gland via IL-6 class inflammatory cytokines (e.g. LIF and OSM). JAK1 and JAK2, which are expressed in the mammary gland, are thought to have redundant functions. However, our previous studies demonstrated that JAK2 is exclusively required for the activation of STAT5 as well as the growth and functional differentiation of the gland. In contrast to the general paradigm, JAK2 might be dispensable for the activation of STAT3 in response to IL-6 class inflammatory cytokines. Utilizing the recently generated JAK1 conditional knockout mouse model, we demonstrate that Janus kinase 1 is the essential kinase responsible for mediating inflammatory cytokine signaling in the mammary gland, specifically during postlactational remodeling events where the absence of JAK1 delayed involution. Ablation of JAK1 in the mammary epithelium of mice dramatically prevented the activation of STAT3 and uncoupled signaling of IL-6 class ligands such as OSM and LIF from their downstream effectors. Completing the profile of STATs, JAK1 was also found to play a non-redundant role in the activation of STAT1 and STAT6 but not STAT5.

Building on the evidence that JAK1 contributes to the activation of STAT3 in non-transformed mammary epithelial cells, we next tested if JAK1 maintained discretion in the activation of STAT3 in neoplastic tissue. A notorious transcription factor, active STAT3 has been tightly linked to aggressive disease, promoting a metastatic phenotype in breast cancers, notably, a subset of which that overexpress the human epidermal growth factor ErbB2/Her2. Using the mammary-specific deletion of JAK1 in the context of ErbB2 oncogenesis, we found that while JAK1 does not affect the tumor onset, it dramatically decreases STAT3 activity and occurrence of metastasis. Interestingly, we found that JAK1 is also required for the tumor-initiating cell population of established disease.

Collectively, the results of these studies describe the novel role of Janus kinase 1 specifically in mammary gland development and the contribution of JAK1 to disease progression.

Available for download on Sunday, June 03, 2018

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