SERUM AUTOANTOBODIES BLOCK CANCER INVASION IN 3D ORGANOTYPIC CULTURE

Autoimmune diseases are caused at least in part by autoantibody-mediated immune responses. Several studies have reported altered risks for developing cancer in patients with autoimmune diseases. In breast cancer patients, the appearance of autoantibodies is temporally associated with the onset of malignant disease (Shah et al., 2010). However, the function of these autoantibodies in tumor progression remains unclear. Recent work from our laboratory shows that breast cancer invasion is led by specialized cancer cells that express cytokeratin-14 (K14). Interestingly, preliminary data from the Rosen laboratory detected autoantibodies against K14 in the serum of patients with autoimmune disease. Based on these data, we raised the specific hypothesis that autoantibodies directly limit tumor progression and metastatic spread by binding to tumor antigens on invasive cancer cells. We show here that purified IgGs from the sera of lupus, dermatomyositis and scleroderma patients bind human mammary tumor antigens and some of these autoantibodies (13200, 12106, and SLE1269) reduce tumor invasion in a 3D organotypic culture system. Furthermore, autoantibodies from patients with no cancer are more effective at blocking tumor invasion when compared to corresponding antibodies from cancer patients. The work described in this thesis presents the first experimental evidence implicating therapeutic roles of patient-derived autoantibodies in blocking breast tumor invasion. Additionally, targets of these antibodies may provide lead candidates for therapeutic targeting of breast cancer metastasis