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Breast Cancer Research and Treatment

, Volume 111, Issue 3, pp 439–448 | Cite as

JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer

  • Michael Reedijk
  • Dushanthi Pinnaduwage
  • Brendan C. Dickson
  • Anna Marie Mulligan
  • Hui Zhang
  • Shelley B. Bull
  • Frances P. O’Malley
  • Sean E. Egan
  • Irene L. Andrulis
Preclinical Study

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.

Keywords

Jagged Notch Node-negative HER2 Disease free survival 

Notes

Acknowledgments

The authors would like to thank Keli Xu, Brenda Cohen and other members of the Egan and Andrulis laboratories for valuable advice and support. The authors also gratefully acknowledge the technical expertise of Suzanna Tjan and the contributions of the Toronto Breast Cancer Group to this work. This work was supported by the National Cancer Institute of Canada with funds from the Terry Fox Run (S.B.B, F.P.O’M., S.E.E, I.L.A) as well as by the Canadian Breast Cancer Foundation (S.E.E. and M.R.). M.R. is supported by the Society of University Surgeons. S.B.B. is supported by a Senior Investigator award from the Canadian Institutes of Health Research and by project funds from the NCE in Mathematics (MITACS). Finally, we thank the patients for their generous donation of tumor samples used in this study.

Supplementary material

10549_2007_9805_MOESM1_ESM.pdf (19 kb)
(PDF 19 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Michael Reedijk
    • 1
    • 2
    • 3
  • Dushanthi Pinnaduwage
    • 4
  • Brendan C. Dickson
    • 5
  • Anna Marie Mulligan
    • 5
  • Hui Zhang
    • 2
  • Shelley B. Bull
    • 6
    • 7
  • Frances P. O’Malley
    • 5
    • 8
  • Sean E. Egan
    • 2
    • 9
  • Irene L. Andrulis
    • 4
    • 5
    • 8
    • 9
  1. 1.Department of Surgical Oncology, University Health Network, Department of SurgeryUniversity of TorontoTorontoCanada
  2. 2.Program in Developmental and Stem Cell BiologyHospital for Sick ChildrenTorontoCanada
  3. 3.Campbell Family Institute for Breast Cancer ResearchPrincess Margaret HospitalTorontoCanada
  4. 4.Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  5. 5.Department of Pathology and Laboratory MedicineMount Sinai HospitalTorontoCanada
  6. 6.Prosserman Center for Health Research, Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  7. 7.Department of Public Health SciencesUniversity of TorontoTorontoCanada
  8. 8.Department of Pathobiology and Laboratory MedicineUniversity of TorontoTorontoCanada
  9. 9.Department of Molecular GeneticsUniversity of TorontoTorontoCanada

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