Abstract PO-129: High expression of MKK3 correlates with poor clinical outcomes in African American breast cancer patients

Abstract

Abstract African American women experience a 2-fold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. Previous studies have revealed a higher frequency of inactivating mutations in multiple tumor suppressor genes in African American breast cancer patients as compared to White patients. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutically actionable targets have been proposed. To address this clinical need, we took the computational systems biology approach to uncover new potentially druggable genes that contribute in poor clinical outcomes of African American breast cancer patients. Through a comprehensive analysis of gene expression and survival data determined for The Cancer Genome Atlas (TCGA) breast cancer patient cohort, we found that more than 30% of all protein-coding genes are differentially expressed in White and African American breast cancer patients. The cluster analysis of co- regulated genes combined with the pathway enrichment analysis revealed a strong association of genes upregulated in African American patients with major oncogenic processes including cell cycle regulation, immunodeficiency, and oxidative phosphorylation. We have further identified more than 30 genes whose overexpression correlates with worsened clinical outcomes of African American breast cancer patients but not White patients. Among those genes, the overexpression of mitogen-activated protein kinase kinase 3 (MKK3) has one of the most dramatic and race-specific impacts on the survival of African American TNBC patients. We found that MKK3 can promote the TNBC tumorigenesis in African American patients in part by activating the master regulator MYC through protein- protein interaction. Together, this study uncovered new genetic features and molecular mechanisms of breast cancer tumorigenesis. As one example, we discovered new functional connectivity between poor clinical outcomes of African American TNBC patients and activation of the MYC transcriptional program through MKK3 signaling. These findings may open new opportunities for clinical investigations to reduce the survival disparity in breast cancer. Citation Format: Xuan Yang, Mohamed Amgad, Lee A.D. Cooper, Yuhong Du, Haian Fu, Andrey A. Ivanov. High expression of MKK3 correlates with poor clinical outcomes in African American breast cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-129.