NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations

<p>Abstract</p> <p>Background</p> <p>A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER)⁺versus ER^-cancer.</p> <p>Results</p> <p>We found association between SNP rs11249433 and expression of the <it>NOTCH2 </it>gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of <it>NOTCH2 </it>was found to be lowest in tumors with <it>TP53 </it>mutations and highest in <it>TP53 </it>wild-type/ER⁺tumors (p = 0.0059). In the latter group, the <it>NOTCH2 </it>expression was particularly increased in carriers of the risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p = 0.0062). Similar association between <it>NOTCH2 </it>expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015), but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of <it>NOTCH2</it>, a truncated version of <it>NOTCH2 </it>consisting of only the extracellular domain.</p> <p>Conclusion</p> <p>This is the first study to show that the expression of <it>NOTCH2 </it>differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER⁺luminal cells in the breast. Therefore, increased expression of <it>NOTCH2 </it>in carriers of rs11249433 may promote development of ER⁺luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of <it>NOTCH2 </it>expression by rs11249433 and the role of <it>NOTCH2 </it>splicing forms in breast cancer development.</p