The risk variant rs11836367 contributes to breast cancer onset and metastasis by attenuating Wnt signaling via regulating NTN4 expression

Most genome-wide association study (GWAS)-identified breast cancer-associated causal variants remain uncharacterized. To provide a framework of understanding GWAS-identified variants to function, we performed a comprehensive study of noncoding regulatory variants at the locus (12q22) and gene in bre...

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Published in:Science advances 2022-06, Vol.8 (23), p.eabn3509
Main Authors: Yang, Han, Ting, Xia, Geng, Yue-Hang, Xie, Yuntao, Nierenberg, Jovia L, Huo, Yan-Fei, Zhou, Yan-Ting, Huang, Yang, Yu, Yu-Qing, Yu, Xin-Yao, Li, Xiao-Fei, Ziv, Elad, Zhang, Hongquan, Fang, Wei-Gang, Shen, Yin, Tian, Xin-Xia
Format: Article
Language:English
Subjects:
Alleles
Animals
Biomedicine and Life Sciences
Cancer
Genetic Predisposition to Disease
Genome-Wide Association Study
Human Genetics
Mice
Neoplasms - genetics
Netrins - genetics
Netrins - metabolism
Polymorphism, Single Nucleotide
SciAdv r-articles
Wnt Signaling Pathway - genetics
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Summary:Most genome-wide association study (GWAS)-identified breast cancer-associated causal variants remain uncharacterized. To provide a framework of understanding GWAS-identified variants to function, we performed a comprehensive study of noncoding regulatory variants at the locus (12q22) and gene in breast cancer etiology. We find that rs11836367 is the more likely causal variant, disrupting enhancer activity in both enhancer reporter assays and endogenous genome editing experiments. The protective T allele of rs11837367 increases the binding of GATA3 to the distal enhancer and up-regulates expression. In addition, we demonstrate that loss of gene in mice leads to tumor earlier onset, progression, and metastasis. We discover that , as a tumor suppressor, can attenuate the Wnt signaling pathway by directly binding to Wnt ligands. Our findings bridge the gaps among breast cancer-associated single-nucleotide polymorphisms, transcriptional regulation of , and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abn3509