CONTRIBUTIONS OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION PROTEINS TO TUMOR-ASSOCIATED MACROPHAGE FUNCTION IN BREAST CANCER

Abstract

The Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is activated in breast cancer and when hyperactive, can influence uncontrollable proliferation and inflammation. Therapies in clinical trials for breast cancer aim to inhibit JAK/STAT to turn off the “switch” in tumors signaling for growth and proliferation. The studies performed in this dissertation investigate how these inhibitors impact the tumor microenvironment. We have demonstrated that although inhibition of the JAK/STAT pathway may act on primary tumor cells directly, this alters a delicate balance in the microenvironment that leads to macrophage-mediated tumor cell therapeutic resistance and proliferation. Using genetic models of STAT3 or STAT5-specific deletion, we sought to determine the contributions of these individual transcription factors to macrophage function in the tumor microenvironment. As it has not be well-studied in breast cancer to date, we further investigated how STAT5 signaling regulates tumor-associated macrophages. We demonstrated disruption of STAT5 signaling in macrophages impedes their expression of genes associated with the anti-tumor immune response, as well as increased factors related to tissue remodeling and enhanced metastatic processes. Taken all together, these studies demonstrate the critical role macrophages play in influencing the progression or restraint of the spread of breast cancer. Further understanding how specific JAK/STAT signaling components control pro- and anti-tumor responses in these cells will be vital for determining a patient’s treatment course as well as allowing for the potential discovery of novel therapeutics.