An enhancer variant associated with breast cancer susceptibility in Black women regulates TNFSF10 expression and antitumor immunity in triple-negative breast cancer.
An enhancer variant associated with breast cancer susceptibility in Black women regulates TNFSF10 expression and antitumor immunity in triple-negative breast cancer.
复制标题
DOI：
10.1093/hmg/ddac168
复制
发表时间：
2023-01-01
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
--
作者：
非洲血统的妇女是所有种族群体中三阴性乳腺癌（TNBC）死亡率最高的。为了了解人群中乳腺癌的基因组基础，我们以前进行了全基因组关联研究，并确定了与黑人女性乳腺癌相关的单核苷酸多态性（SNP）。在这项研究中，我们调查了顶部相关SNP rs 13074711的功能意义。我们发现SNP作为增强子变体并调节TNBC细胞中TNFSF 10（TRAIL）的表达，SNP基因型与乳腺肿瘤中TNFSF 10表达之间存在显著相关性。在机制上，rs 13074711调节c-MYB在基序处的结合活性，从而控制TNFSF 10的表达。有趣的是，与欧洲裔美国人相比，非洲裔美国人在许多癌症中的TNFSF 10表达一直较低。此外，TNFSF 10在TNBC中的表达与抗病毒免疫基因的表达显著相关，并受I型干扰素（IFN）的调节。因此，TNFSF 10的损失导致响应于I型IFN和poly（I：C）（双链病毒的合成类似物）的TNBC细胞凋亡的显著减少。最后，在乳腺癌的同基因小鼠模型中，乳腺肿瘤中TNFSF 10缺乏降低了肿瘤浸润的CD 4+和CD 8 + T细胞数量。总的来说，我们的研究结果表明，TNFSF 10在TNBC抗病毒免疫反应的调节中起着重要作用，并且表达部分受到与黑人女性乳腺癌相关的遗传变异的调节。我们的研究结果强调了遗传变异对免疫防御机制的重要贡献。
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 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 compared with European Americans. Furthermore, TNFSF10 expression in TNBC was significantly correlated with the 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.
登录
查看更多内容
影响因子：
64.8
作者：
Simoni, Yannick;Becht, Etienne;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
--
作者：
Lee HJ;Kim YA;Sim CK;Heo SH;Song IH;Park HS;Park SY;Bang WS;Park IA;Lee M;Lee JH;Cho YS;Chang S;Jung J;Kim J;Lee SB;Kim SY;Lee MS;Gong G
通讯作者：
Gong G
影响因子：
158.5
作者：
Schmid, P.;Adams, S.;Emens, L. A.
通讯作者：
Emens, L. A.
影响因子：
11.2
作者：
Fend, Laetitia;Yamazaki, Takahiro;Zitvogel, Laurence
通讯作者：
Zitvogel, Laurence
DOI：
10.1038/nri.2017.49
发表时间：
2017-09
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Nagarsheth N;Wicha MS;Zou W
通讯作者：
Zou W