Purpose: Black women experience the highest breast cancer mortality rate compared to women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry. Experimental Design: We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n=182) and the University of Chicago (n=161). We also analyzed RNA sequencing data from Nigeria (n=84) and TCGA datasets (n=863). Patient prognosis was analyzed using multiple datasets. Results: The VEGF-hypoxia signature was highest in the basal-like subtype compared to other subtypes, with greater expression in Black women compared to White women. In the TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared to non-necrosis tumors (p<0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation and necrosis. T cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in the TCGA dataset. Lastly, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (p<0.0001) and SCAN-B datasets (p=0.002). Conclusions:These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora.

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