There is no cure for metastatic prostate cancer (PCa), and about 1 in 41 men in the United States (U.S.) will die of the disease. Since African American (AA) men are most likely to be diagnosed with metastatic PCa, the expansion of research studies that thoroughly evaluate the molecular mechanisms which drive PCa progression and metastasis leading to lethal outcomes in AA men remains a paramount goal. Metastatic PCa initially responds to suppression of androgen signaling through androgen deprivation therapy. However, relapse is inevitable and treatment options are limited. For this reason, a promising area of investigation focuses on inhibiting androgen-independent signaling pathways—such as human epidermal growth factor receptor 2 (HER2)—that promote metastasis. HER2 overexpression is remarkably frequent in PCa tumors and correlates with worse prognosis and treatment-resistance in PCa patients but has not been evaluated in studies with sufficient recruitment of HER2 positive patients or in studies inclusive of AA PCa patients or biospecimens. This research proposal is the first to investigate HER2 by race and evaluate its role in PCa outcome disparities. Preliminary analysis of RNA sequencing and immunohistochemistry of prostate tissue reveals HER2 overexpression in AA PCa patients and suggests a positive correlation with West African ancestry (WAA). We hypothesize that unique multiomic signatures contribute to HER2 overexpression in AA patients which worsens clinical features, treatment response, and survival outcomes to be evaluated with these aims: Aim 1: Confirm that HER2/ERBB2 overexpression is positively correlated with WAA and associated with worse tumor biology, disease stage, clinical features, treatment response, and survival outcomes. The effects of HER2/ERBB2 overexpression on cellular function and tumor biology will be evaluated in cells and 3D cultures. Correlations between HER2 overexpression and disease stage, clinical features, treatment response, and survival outcomes will be assessed in tumor tissue. All analyses will compare HER2 expression with WAA calculated using validated ancestry informative markers through single nucleotide polymorphism genotyping. Aim 2: Identify genetic variations associated with HER2/ERBB2 amplification using liquid biopsy. Circulating tumor cells isolated from patients with metastatic PCa will be characterized to identify genetic variations associated with HER2/ERBB2 amplification using single cell genomics. Aim 3: Determine multiomic signatures associated with HER2/ERBB2 overexpression. Epigenetic, transcriptomic, and proteomic analyses will be performed in cell lines and sera to identify unique signatures associated with HER2/ERBB2 overexpression that are predictive of treatment-resistance and poor survival. Relevance: Thorough evaluation of the molecular mechanisms by which HER2/ERBB2 overexpression steers PCa progression and treatment-resistance will provide the foundation to pursue future clini...