title: NOTCH2 in breast cancer: association of SNP rs11249433 with gene expression in ER-positive breast tumors without TP53 mutations.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Fu
authors.forename: Hege
authors.initials: H
authors.lastname: Edvardsen
authors.forename: Alpana
authors.initials: A
authors.lastname: Kaushiva
authors.forename: Juan P
authors.initials: JP
authors.lastname: Arhancet
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Howe
authors.forename: Indu
authors.initials: I
authors.lastname: Kohaar
authors.forename: Patricia
authors.initials: P
authors.lastname: Porter-Gill
authors.forename: Anushi
authors.initials: A
authors.lastname: Shah
authors.forename: Hege
authors.initials: H
authors.lastname: Landmark-Høyvik
authors.forename: Sophie D
authors.initials: SD
authors.lastname: Fosså
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
authors.forename: Bjørn
authors.initials: B
authors.lastname: Naume
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D018613:Microscopy, Confocal; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D051883:Receptor, Notch2 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C497764:NOTCH2 protein, human; D020033:Protein Isoforms; D051883:Receptor, Notch2; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53