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

Abstract

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 <i>NTN4</i> locus (12q22) and <i>NTN4</i> 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 <i>NTN4</i> expression. In addition, we demonstrate that loss of <i>NTN4</i> gene in mice leads to tumor earlier onset, progression, and metastasis. We discover that <i>NTN4</i>, 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 <i>NTN4</i>, and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.