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

Autor:	Yang H; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China.; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Ting X; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Geng YH; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Xie Y; Breast Center, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing 100142, China., Nierenberg JL; Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, San Francisco, CA, USA., Huo YF; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Zhou YT; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Huang Y; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Yu YQ; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Yu XY; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Li XF; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Ziv E; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.; Division of General Internal Medicine, Department of Medicine, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA., Zhang H; Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China., Fang WG; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China., Shen Y; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Tian XX; Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2022 Jun 10; Vol. 8 (23), pp. eabn3509. Date of Electronic Publication: 2022 Jun 10.
DOI:	10.1126/sciadv.abn3509
Abstrakt:	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 NTN4 locus (12q22) and NTN4 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 NTN4 expression. In addition, we demonstrate that loss of NTN4 gene in mice leads to tumor earlier onset, progression, and metastasis. We discover that NTN4 , 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 NTN4 , and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.
Databáze:	MEDLINE
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