Abstract 4742: NOTCH2 in breast cancer: Association of SNP rs11249433 with gene expression in ER-positive breast tumors without p53 gene mutations

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 with estrogen receptor (ER)-positive than with ER-negative cancer. We aimed to identify a biologically relevant molecular phenotype of this association. Methods: NOTCH2 expression was measured with custom-designed TaqMan assays on 226 breast tumor samples and 319 blood samples of breast cancer patients. PANTHER analysis based on expression in NCI-60 cell lines (Affymetrix HG-U133 arrays) was used to examine enrichment of pathways, biological processes, or molecular functions for transcripts significantly correlated with NOTCH2 expression. Results: We found evidence of a functional relationship between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. NOTCH2 expression differed in subgroups of 226 breast tumor samples, being lowest in tumors with mutations in the p53 gene and highest in p53 wild-type/ER-positive tumors (p=0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p=0.0062). This effect is tissue-specific since rs11249433 was not associated with NOTCH2 expression in blood samples of 319 breast cancer patients. Pathway enrichment analysis of NOTCH2 in the NCI-60 cell lines indicated role of NOTCH2 in integrin signaling, cell-cell interactions, and cell structure and motility. Conclusion: This is the first study to explain genetic association between SNP rs11249433 and breast cancer risk by showing that NOTCH2 expression in breast tumors differs in subgroups of patients and between patients with the risk rs11249433 genotypes when compared to the non-risk genotype. The NOTCH pathway has key functions in stem cell differentiation of ER-positive luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER-positive luminal ductal tumors. The exact mechanisms of regulation of NOTCH2 expression by rs11249433 as well as the role of NOTCH2 in breast cancer development remain to be determined. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl