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

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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.

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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.

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Author notes

  1. Michael Reedijk

    Present address: Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, 7th Floor, Suite 706, 620 University Avenue, Toronto, ON, Canada, M5G 2M9

Authors and Affiliations

  1. Department of Surgical Oncology, University Health Network, Department of Surgery, University of Toronto, Toronto, ON, Canada, M5G 2M9

    Michael Reedijk

  2. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, The Toronto Medical Discovery Tower, 101 College Street, Toronto, ON, Canada, M5G 1L7

    Michael Reedijk, Hui Zhang & Sean E. Egan

  3. Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 975C-600 University Avenue, Toronto, ON, Canada, M5G 1X5

    Dushanthi Pinnaduwage & Irene L. Andrulis

  4. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada

    Brendan C. Dickson, Anna Marie Mulligan, Frances P. O’Malley & Irene L. Andrulis

  5. Prosserman Center for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Shelley B. Bull

  6. Department of Public Health Sciences, University of Toronto, Toronto, Canada

    Shelley B. Bull

  7. Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Canada

    Frances P. O’Malley & Irene L. Andrulis

  8. Department of Molecular Genetics, University of Toronto, Toronto, Canada

    Sean E. Egan & Irene L. Andrulis

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  1. Michael Reedijk
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  2. Dushanthi Pinnaduwage
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  8. Sean E. Egan
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  9. Irene L. Andrulis
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Corresponding authors

Correspondence to Sean E. Egan or Irene L. Andrulis.

Additional information

M. Reedijk and D. Pinnaduwage contributed equally to this work.

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Reedijk, M., Pinnaduwage, D., Dickson, B.C. et al. JAG1 expression is associated with a basal phenotype and recurrence in lymph node-negative breast cancer. Breast Cancer Res Treat 111, 439–448 (2008). https://doi.org/10.1007/s10549-007-9805-3

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  • DOI: https://doi.org/10.1007/s10549-007-9805-3

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