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Background  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.    Results  We found association between SNP rs11249433 and expression of the  NOTCH2  gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of  NOTCH2  was found to be lowest in tumors with  TP53  mutations and highest in  TP53  wild-type/ER +  tumors (p = 0.0059). In the latter group, the  NOTCH2  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  NOTCH2  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  NOTCH2 , a truncated version of  NOTCH2  consisting of only the extracellular domain.    Conclusion  This is the first study to show that the expression of  NOTCH2  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  NOTCH2  in carriers of rs11249433 may promote development of ER +  luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of  NOTCH2  expression by rs11249433 and the role of  NOTCH2  splicing forms in breast cancer development.

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