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High-level Coexpression of JAG1 and NOTCH1 Is Observed in Human Breast Cancer and Is Associated with Poor Overall Survival

¹ Programs in Developmental Biology and Cancer Research, The Hospital for Sick Children; ² Department of Surgery, Mount Sinai Hospital; Departments of ³ Surgical Oncology, ⁴ Pathology, and ⁵ Clinical Study Coordination and Biostatistics, Princess Margaret Hospital, University Health Network; and ⁶ Department of Molecular and Medical Genetics, The Faculty of Medicine, The University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Sean E. Egan, Program in Developmental Biology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G-1X8. Phone: 416-813-5267; Fax: 416-813-8883; E-mail: segan{at}sickkids.ca.

Aberrant activation of Notch receptors has been shown to cause mammary tumors in mice. We therefore used in situ hybridization to analyze expression of Notch ligands and receptors in human breast cancer. High levels of JAG1 and NOTCH1 were noted in a subset of tumors with poor prognosis pathologic features (P < 0.05). We therefore used tissue microarrays to analyze the expression of these genes in a collection of breast cancers from patients representing a wide spectrum of clinical stages, and from whom associated follow-up survival data was available (n = 184). Patients with tumors expressing high levels of JAG1 or NOTCH1 had a significantly poorer overall survival compared with patients expressing low levels of these genes [5-year survival rate of 42% versus 65% and median survival of 50 versus 83 months, respectively, for JAG1^{Hi vs. Lo} (P = 0.01); 49% versus 64% and 53 versus 91 months, respectively, for NOTCH1^{Hi vs. Lo} (P = 0.02)]. Moreover, a synergistic effect of high-level JAG1 and high-level NOTCH1 coexpression on overall survival was observed (5-year survival rate of 32% and median survival of 40 months; P = 0.003). These data (a) identify novel prognostic markers for breast cancer, (b) suggest a mechanism whereby Notch is activated in aggressive breast tumors, and (c) may identify a signaling pathway activated in poor prognosis breast cancer which can be therapeutically targeted.

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