High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients

• Published in: Journal of translational medicine 2020-09, Vol.18 (1), p.334-19, Article 334
• Main Authors: Yang, Xuan, Amgad, Mohamed, Cooper, Lee A D, Du, Yuhong, Fu, Haian, Ivanov, Andrey A
• Format: Article
• Language: English
• Subjects: African American women; African Americans; Black or African American - genetics; Breast cancer; Breast Neoplasms - genetics; Cancer genetics; Cancer patients; Care and treatment; Cell Transformation, Neoplastic; Clinical outcomes; Differential expression; Female; Gene expression; Genes; Genetic aspects; Genetic research; Genomes; Genomics; Humans; Incidence; Invasiveness; Kinases; MAP kinase; Mesenchyme; Mitogens; MKK3; MKK3 protein; Mortality; Mutation; Myc protein; Patient outcomes; Protein kinase; Protein kinases; Protein-protein interactions; Racial disparity; RNA; Survival; Triple Negative Breast Neoplasms - genetics; Triple-negative breast cancer; Tumorigenesis; White People - genetics
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-020-02502-w

African American women experience a twofold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutic targets have been proposed. To address this knowledge gap, we performed a systematic analysis of the relationship between gene mRNA expression and clinical outcomes determined for The Cancer Genome Atlas (TCGA) breast cancer patient cohort. The systematic differential analysis of mRNA expression integrated with the analysis of clinical outcomes was performed for 1055 samples from the breast invasive carcinoma TCGA PanCancer cohorts. A deep learning fully-convolutional model was used to determine the association between gene expression and tumor features based on breast cancer patient histopathological images. We found that more than 30% of all protein-coding genes are differentially expressed in White and African American breast cancer patients. We have determined a set of 32 genes whose overexpression in African American patients strongly correlates with decreased survival of African American but not White breast cancer patients. Among those genes, the overexpression of mitogen-activated protein kinase kinase 3 (MKK3) has one of the most dramatic and race-specific negative impacts on the survival of African American patients, specifically with triple-negative breast cancer. We found that MKK3 can promote the TNBC tumorigenesis in African American patients in part by activating of the epithelial-to-mesenchymal transition induced by master regulator MYC. The poor clinical outcomes in African American women with breast cancer can be associated with the abnormal elevation of individual gene expression. Such genes, including those identified and prioritized in this study, could represent new targets for therapeutic intervention. A strong correlation between MKK3 overexpression, activation of its binding partner and major oncogene MYC, and worsened clinical outcomes suggests the MKK3-MYC protein-protein interaction as a new promising target to reduce racial disparity in breast cancer survival.