title: JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer.
abstract: Expression of the JAG1 Notch ligand has previously been shown to correlate with poor overall survival in women with advanced breast cancer. We undertook to test whether expression of JAG1 is associated with reduced disease free survival (DFS) in 887 samples from a prospectively accrued LNN cohort with a median follow-up greater than 8 years. Moderate to high JAG1 mRNA expression was associated with reduced DFS in univariate analysis (hazard ratio of 1.58; 95% confidence interval, 1.03-2.40; P = 0.034) and correlated with large tumor size, ER and PgR negativity, high tumor grade, and p53 antibody reactivity. Although elevated risk of reduced DFS in patients with high JAG1 mRNA did not persist with adjustment for other prognostic factors, it did in combination with HER2. JAG1 mRNA was positively associated with expression of basal breast cancer markers, however, in contrast to the finding that basal gene expression is most strongly associated with reduced DFS in the first 36 months of follow-up, JAG1 mRNA expression was associated with reduced DFS through the full follow-up period. Also, tumors expressing high levels of both mRNA and protein showed reduced DFS as compared to all other groups in univariate analysis (hazard ratio of 1.73; 95% confidence interval, 1.09-2.74; P = 0.020). Thus, JAG1 expression is associated with poor DFS in LNN breast cancer. As JAG1 is a target of several oncogenic signaling pathways, and is a ligand for Notch, these data provide novel insights into signaling that may contribute to progression of early stage breast cancer.
authors.affiliation: Department of Surgical Oncology, University of Toronto, Toronto, ON, Canada, M5G 2M9.
authors.forename: Michael
authors.initials: M
authors.lastname: Reedijk
authors.forename: Dushanthi
authors.initials: D
authors.lastname: Pinnaduwage
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Dickson
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Mulligan
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Bull
authors.forename: Frances P
authors.initials: FP
authors.lastname: O'Malley
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002135:Calcium-Binding Proteins / Q000032:analysis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis* / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000032:analysis* / Q000235:genetics; D008875:Middle Aged; D018295:Neoplasms, Basal Cell / Q000737:chemistry* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009864:Ontario; D010641:Phenotype; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012008:Recurrence; D000072099:Serrate-Jagged Proteins; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000072099:Serrate-Jagged Proteins; C000606273:JAG1 protein, human; C508053:ERBB2 protein, human