SUMMARY Late stages of cancer metastasis involves the seeding of cancer cells at distant organs and the lethaloutgrowth of seeded cells. In 2019 virtually all 31620 prostate cancer (PCa) deaths in the United States wereattributed to metastasis. Epithelial Mesenchymal Transition (EMT) is important for physiological development;however EMT promotes migration invasion and seeding in multiple cancer types. In contrast EMT inhibitsproliferation and tumor outgrowth. SNAI1 and Twist1 are major EMT drivers that promote cancer cell seedingand inhibit cell proliferation and tumor outgrowth in non-PCa. SNAI1 expression is detected in invasive primaryand metastatic PCa. In contrast the androgen receptor (AR) is a major driver of PCa cell proliferation and tumoroutgrowth. Of note AR activates but SNAI1 represses transcription of Cyclin D1 (a cell cycle driver). Both bindto an overlapping region of the ccnd1 (Cyclin D1) proximal promoter suggesting direct competitive regulation ofCyclin D1 transcription. Given that outgrowth occurs at the end of the metastasis cascade EMT is likely to occurtransiently early in PCa patients. In fact vimentin (a marker of EMT) is highly expressed in PCa circulating tumorcells; however vimentin is lowly expressed once seeded PCa cells grow into detectable metastases. While EMTand AR signaling have been independently investigated in PCa how EMT and AR coordinate PCa metastasisremains unclear. Adhering to the transient nature of EMT in clinical PCa a TetON-SNAI1 expression systemwas created whereby transient expression of SNAI1 can be turned ON/OFF with doxycycline. Preliminary datashows that SNAI1 induces a mesenchymal morphology in PCa cells suppresses cell growth and upregulatesmRNA of EMT markers such as vimentin and NPR2. However AR signaling suppresses SNAI1s ability toupregulate vimentin and NRP2 and downregulates Twist1 mRNA independent of SNAI1 expression. Altogetherthese data suggest that AR and SNAI1 have opposing roles in regulating EMT and proliferation; and areconsistent with the late sequence of events that occur during PCa metastasis: i.e. seeding followed byoutgrowth. Therefore I hypothesize that SNAI1 mediates an anti-proliferative EMT-like invasion program topromote PCa seeding; subsequently AR antagonizes SNAI1-mediated cyclin D1 repression to restoreproliferation and promote metastatic outgrowth. The following aims are designed to address the centralhypothesis. Aim1: Determine how AR impacts SNAI1s ability to promote PCa invasion and metastatic seeding.Aim2: Determine how SNAI1 and AR regulate PCa proliferation. Aim3: Determine extent of AR and SNAI1 co-expression and activity in clinical PCa samples. Patients with aggressive PCa are treated with standard anti AR-signaling therapies; but will develop resistance within 2 years. Given the limited treatment options available forthis group of patients further study of SNAI1 and AR will help develop research models that are more clinicallyaccurate and provide deeper insights for future therapeutic strategies.