An enhancer variant associated with breast cancer susceptibility in Black women regulates TNFSF10 expression and antitumor immunity in triple-negative breast cancer

Abstract

Women of African ancestry have the highest mortality from triple-negative breast cancer (TNBC) of all racial groups. To understand the genomic basis of breast cancer in the populations, we previously conducted genome-wide association studies (GWAS) and identified single nucleotide polymorphisms (SNPs) associated with breast cancer in Black women. In this study, we investigated the functional significance of the top associated SNP rs13074711. We found the SNP served as an enhancer variant and regulated TNFSF10 (TRAIL) expression in TNBC cells, with a significant association between the SNP genotype and TNFSF10 expression in breast tumors. Mechanistically, rs13074711 modulated the binding activity of c-MYB at the motif and thereby controlled TNFSF10 expression. Interestingly, TNFSF10 expression in many cancers was consistently lower in African Americans (AA) compared to European Americans (EA). Furthermore, TNFSF10 expression in TNBC was significantly correlated with expression of antiviral immune genes and was regulated by type I interferons (IFNs). Accordingly, loss of TNFSF10 resulted in a profound decrease in apoptosis of TNBC cells in response to type I IFNs and poly (I:C), a synthetic analogue of double stranded virus. Lastly, in a syngeneic mouse model of breast cancer, TNFSF10-deficiency in breast tumors decreased tumor-infiltrated CD4+ and CD8+ T cell quantities. Collectively, our results suggested that TNFSF10 plays an important role in the regulation of antiviral immune responses in TNBC, and the expression is in part regulated by a genetic variant associated with breast cancer in Black women. Our results underscore the important contributions of genetic variants to immune defense mechanisms.

RNA splicing regulator EIF3D regulates the tumor microenvironment through immunogene-related alternative splicing in head and neck squamous cell carcinoma

“…Notably, immune-related genes such as TNFSF10, NEDD4, HSPA2, MMP12, CDKN1A, and NGFR exhibited reduced expression, while FABP5, ISG20L2, OGFR, AEN, CCN2, and GSEC showed increased expression. For instance, TNFSF10-deficiency in breast tumors has been linked to decreased tumor-infiltrating CD4+ and CD8+ T cells in a mouse model of breast cancer [ 45 ]. High NEDD4 expression in melanoma tissue is associated with poor patient prognosis and promotes tumor progression by inhibiting T-cell-mediated killing of melanoma cells [ 46 ].…”

Osteosarcoma neutrophil extracellular trap network-associated gene recurrence and metastasis model

“…Numerous studies have reported an association between TNFSF10 and the progression of osteosarcoma (Kamihara et al 2020 ). The findings of Yoo Jane Han suggest that TNFSF10 plays an important role in regulating the antiviral immune response in triple-negative breast cancer (TNBC) (Han et al 2022 ). One study identified ETS2 inhibition as a potential therapeutic target for p53 mutant osteosarcoma (Pourebrahim et al 2017 ).…”

A joint transcriptome-wide association study across multiple tissues identifies new candidate susceptibility genes for breast cancer

“…A recently published study deleted the TNFSF10 gene from TNBC cells using CRISPR-Cas9 technology and stimulated cells with either poly (I:C), a synthetic analogue of double-stranded RNA virus, or IFN-β, and found that depletion of TNFSF10 clearly reduced poly (I:C)-induced or IFN-β-induced apoptosis 39 . Furthermore, the researcher edited rs13074711, the risk variant reported in previous GWAS 38 , using CRISPR-Cas9 technology, and found it altered TNFSF10 expression and IFN-β-induced apoptosis 39 . Taken together, there is strong evidence that TNFSF10 is a possible cancer suppressor responsible for GWAS signal in 3q26.21 through immune defense mechanisms.…”