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

Xuan Yang,Lee A D Cooper,Haian Fu,Yuhong Du,Andrey A Ivanov,Mohamed Amgad

doi:10.1186/s12967-020-02502-w

Xuan Yang, Lee A D Cooper + Show 4 more

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https://doi.org/10.1186/s12967-020-02502-w

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Abstract

BackgroundAfrican 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.MethodsThe 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.ResultsWe 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.ConclusionsThe 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.

Highlights

We found that 7195 genes showed statistically significant differences in expression between White and Black/ African American cohorts, as determined with the Wilcoxon test p-values adjusted for the false discovery rate (q-value < 0.001, Additional file 1: Table S1)
Through the enrichment analysis of signaling and metabolic pathways defined in the KEGG database [24], we found that overexpressed BAAhigh genes (BAAOVR genes) showed the enrichment in genes associated with several major oncogenic pathways
Through the integrative statistical analyses of clinical and genomics data, we identified 32 genes as putative targets for therapeutic intervention in Black or African American breast cancer patients

Summary

Introduction

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. Recent studies have shown up to a twofold higher incidence of triple-negative breast cancer (TNBC) among African American women as compared to White women [2–4]. Previous studies have revealed significant differences in the mutation rates of several cancer driver genes in African American and White breast cancer patients (Table 1) [9–13]. Mutations in the catalytic subunit of the Alpha isoform of the Phosphatidylinositol 4,5-Bisphosphate 3-Kinase (PIK3CA) were rarer in African American patients than in White breast cancer patients (20% vs 34%). This difference was even more significant between European White patients (36%) and a cohort of Nigerian breast cancer patients (17%) [13]. In the same study [13], Pitt et al determined a significantly lower mutation rate of Cadherin 1 (CDH1) in Nigerian patients (0.8%) and TCGA African American patients (6.4%) as compared to White patients (16.2%)

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