Publications by authors named "Michael Reedijk"

29 Publications

  • Page 1 of 1

Notch Signaling and the Breast Cancer Microenvironment.

Adv Exp Med Biol 2021 ;1287:183-200

Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Notch promotes breast cancer progression through tumor initiating cell maintenance, tumor cell fate specification, proliferation, survival, and motility. In addition, Notch is recognized as a decisive mechanism in regulating various juxtacrine and paracrine communications in the tumor microenvironment (TME). In this chapter, we review recent studies on stress-mediated Notch activation within the TME and sequelae such as angiogenesis, extracellular matrix remodeling, changes in the innate and adaptive immunophenotype, and therapeutic perspectives.
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http://dx.doi.org/10.1007/978-3-030-55031-8_12DOI Listing
October 2020

Landscape mapping of shared antigenic epitopes and their cognate TCRs of tumor-infiltrating T lymphocytes in melanoma.

Elife 2020 04 21;9. Epub 2020 Apr 21.

Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

HLA-restricted T cell responses can induce antitumor effects in cancer patients. Previous human T cell research has largely focused on the few HLA alleles prevalent in a subset of ethnic groups. Here, using a panel of newly developed peptide-exchangeable peptide/HLA multimers and artificial antigen-presenting cells for 25 different class I alleles and greater than 800 peptides, we systematically and comprehensively mapped shared antigenic epitopes recognized by tumor-infiltrating T lymphocytes (TILs) from eight melanoma patients for all their class I alleles. We were able to determine the specificity, on average, of 12.2% of the TILs recognizing a mean of 3.1 shared antigen-derived epitopes across HLA-A, B, and C. Furthermore, we isolated a number of cognate T cell receptor genes with tumor reactivity. Our novel strategy allows for a more complete examination of the immune response and development of novel cancer immunotherapy not limited by HLA allele prevalence or tumor mutation burden.
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http://dx.doi.org/10.7554/eLife.53244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234812PMC
April 2020

Evaluation of Lymphadenopathy and Suspected Lymphoma in a Lymphoma Rapid Diagnosis Clinic.

JCO Oncol Pract 2020 01 1;16(1):e29-e36. Epub 2019 Oct 1.

Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Purpose: Lymphomas often present a diagnostic challenge, and for some a delay in diagnosis can negatively influence outcomes of therapy. We established a nurse practitioner-led lymphoma rapid diagnosis clinic (LRDC) with the goal of reducing wait times to definitive diagnosis. We examined the initial 30-month experience of the LRDC, and results were compared with time periods before implementation of the clinic to determine program impact.

Methods: All patients referred to LRDC with suspicion of lymphoma from June 1, 2015 to Nov 30, 2017 were evaluated. Time from initial consultation to diagnosis was compared with patients diagnosed at our center with lymphoma in 2008 and 2012. Patient symptoms and relevant laboratory/imaging findings were collected to identify patterns of presentation and predictive factors for benign diagnoses.

Results: Of the 126 patients evaluated, 66 (52%) had confirmation of lymphoma diagnosis. Median time to lymphoma diagnosis was 16 days for patients assessed in LRDC and 28 days for historical controls ( < .001). By univariable analysis, lymph node size greater than 3.4 cm and presence of mediastinal or abdominal adenopathy increased the likelihood of a diagnosis of malignancy, whereas younger age, being a nonsmoker, and prior rheumatologic condition were associated with a nonmalignant diagnosis. In multivariable analysis, lymph node size, age, and prior rheumatologic diagnosis remained significant.

Conclusion: Establishing a nurse practitioner-led LRDC was effective in shortening time to diagnosis of lymphoma. Younger age, smaller lymph node size, and prior rheumatologic disorder reduced the likelihood of a cancer diagnosis in our patient population.
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http://dx.doi.org/10.1200/JOP.19.00202DOI Listing
January 2020

Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2.

Cancer Immunol Immunother 2019 May 11;68(5):773-785. Epub 2019 Feb 11.

Tumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Canada.

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vβ chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).
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http://dx.doi.org/10.1007/s00262-019-02307-xDOI Listing
May 2019

Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma.

Clin Cancer Res 2018 11 31;24(22):5685-5696. Epub 2018 Jul 31.

The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Regulatory T (Treg) cells expressing the transcription factor FOXP3 are essential for the maintenance of immunologic self-tolerance but play a detrimental role in most cancers due to their ability to suppress antitumor immunity. The phenotype of human circulating Treg cells has been extensively studied, but less is known about tumor-infiltrating Treg cells. We studied the phenotype and function of tumor-infiltrating Treg cells in ovarian cancer and melanoma to identify potential Treg cell-associated molecules that can be targeted by tumor immunotherapies. The phenotype of intratumoral and circulating Treg cells was analyzed by multicolor flow cytometry, mass cytometry, RNA-seq, and functional assays. Treg cells isolated from ovarian tumors displayed a distinct cell surface phenotype with increased expression of a number of receptors associated with TCR engagement, including PD-1, 4-1BB, and ICOS. Higher PD-1 and 4-1BB expression was associated with increased responsiveness to further TCR stimulation and increased suppressive capacity, respectively. Transcriptomic and mass cytometry analyses revealed the presence of Treg cell subpopulations and further supported a highly activated state specifically in ovarian tumors. In comparison, Treg cells infiltrating melanomas displayed lower FOXP3, PD-1, 4-1BB, and ICOS expression and were less potent suppressors of CD8 T-cell proliferation. The highly activated phenotype of ovarian tumor-infiltrating Treg cells may be a key component of an immunosuppressive tumor microenvironment. Receptors that are expressed by tumor-infiltrating Treg cells could be exploited for the design of novel combination tumor immunotherapies. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0554DOI Listing
November 2018

Notch Shapes the Innate Immunophenotype in Breast Cancer.

Cancer Discov 2017 11 8;7(11):1320-1335. Epub 2017 Aug 8.

Campbell Family Institute for Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment. Here, we show that Notch in tumor cells regulates the expression of two powerful proinflammatory cytokines, IL1β and CCL2, and the recruitment of tumor-associated macrophages (TAM). Notch also regulates TGFβ-mediated activation of tumor cells by TAMs, closing a Notch-dependent paracrine signaling loop between these two cell types. We use a mouse model in which Notch can be regulated in spontaneous mammary carcinoma to confirm that IL1β and CCL2 production, and macrophage recruitment are Notch-dependent. In human disease, expression array analyses demonstrate a striking association between Notch activation, IL1β and CCL2 production, macrophage infiltration, and BLBC. These findings place Notch at the nexus of a vicious cycle of macrophage infiltration and amplified cytokine secretion and provide immunotherapeutic opportunities in BLBC. BLBC is aggressive and has an unmet need for effective targeted treatment. Our data highlight immunotherapeutic opportunities in Notch-activated BLBC. Effective IL1β and CCL2 antagonists are currently in clinical review to treat benign inflammatory disease, and their transition to the cancer clinic could have a rapid impact. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0037DOI Listing
November 2017

Breast cancer recurrence following radioguided seed localization and standard wire localization of nonpalpable invasive and in situ breast cancers: 5-Year follow-up from a randomized controlled trial.

Am J Surg 2017 Apr 20;213(4):798-804. Epub 2016 Oct 20.

Department of Surgery, McMaster University, St. Joseph's Healthcare, Hamilton, ON, Canada. Electronic address:

Background: This study compared 5-year breast cancer (BC) recurrence rates in patients randomized to radioguided seed localization (RSL) or wire localization (WL) for non-palpable BC undergoing breast conserving surgery.

Methods: Chart review of follow-up visits and surveillance imaging was conducted. Data collected included patient and tumour factors, adjuvant therapies and BC recurrence (local recurrence (LR), regional recurrence (RR), and distant metastasis (DM)). Univariate analysis was used.

Results: Follow-up data were available for 298 patients (98%) and median follow-up time was 65 months. There were 11 (4%) cases of BC recurrence and median time to recurrence was 26 months. LR occurred in 8 patients (6 WL and 2 RSL; p = 0.28). Positive margins at first surgery (p = 0.024) and final surgery (p = 0.004) predicted for BC recurrence.

Conclusions: There was no detectable difference in BC recurrence between WL and RSL groups and positive margins at initial or final surgery both predicted for BC recurrence.
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http://dx.doi.org/10.1016/j.amjsurg.2016.06.016DOI Listing
April 2017

Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study.

Breast Cancer Res 2015 Mar 3;17:32. Epub 2015 Mar 3.

Introduction: The antidiabetic drug metformin exhibits potential anticancer properties that are believed to involve both direct (insulin-independent) and indirect (insulin-dependent) actions. Direct effects are linked to activation of AMP-activated protein kinase (AMPK) and an inhibition of mammalian target of rapamycin mTOR signaling, and indirect effects are mediated by reductions in circulating insulin, leading to reduced insulin receptor (IR)-mediated signaling. However, the in vivo impact of metformin on cancer cell signaling and the factors governing sensitivity in patients remain unknown.

Methods: We conducted a neoadjuvant, single-arm, "window of opportunity" trial to examine the clinical and biological effects of metformin on patients with breast cancer. Women with untreated breast cancer who did not have diabetes were given 500 mg of metformin three times daily for ≥2 weeks after diagnostic biopsy until surgery. Fasting blood and tumor samples were collected at diagnosis and surgery. Blood glucose and insulin were assayed to assess the physiologic effects of metformin, and immunohistochemical analysis of tumors was used to characterize cellular markers before and after treatment.

Results: Levels of IR expression decreased significantly in tumors (P = 0.04), as did the phosphorylation status of protein kinase B (PKB)/Akt (S473), extracellular signal-regulated kinase 1/2 (ERK1/2, T202/Y204), AMPK (T172) and acetyl coenzyme A carboxylase (S79) (P = 0.0001, P < 0.0001, P < 0.005 and P = 0.02, respectively). All tumors expressed organic cation transporter 1, with 90% (35 of 39) exhibiting an Allred score of 5 or higher.

Conclusions: Reduced PKB/Akt and ERK1/2 phosphorylation, coupled with decreased insulin and IR levels, suggest insulin-dependent effects are important in the clinical setting. These results are consistent with beneficial anticancer effects of metformin and highlight key factors involved in sensitivity, which could be used to identify patients with breast cancer who may be responsive to metformin-based therapies.

Trial Registration: ClinicalTrials.gov identifier: NCT00897884. Registered 8 May 2009.
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http://dx.doi.org/10.1186/s13058-015-0540-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381495PMC
March 2015

A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: A study of the Princess Margaret, Chicago and California phase II consortia.

Gynecol Oncol 2015 May 11;137(2):216-22. Epub 2015 Mar 11.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Electronic address:

Purpose: A phase II study was performed to evaluate the efficacy and safety of single-agent RO4929097 (a gamma-secretase inhibitor) in patients with recurrent platinum-resistant ovarian cancer.

Experimental Design: Women with progressive platinum-resistant ovarian cancer treated with ≤2 chemotherapy regimens for recurrent disease were enrolled in this trial. Patients received oral RO4929097 at 20 mg once daily, 3 days on/4 days off each week in a three week cycle. The primary endpoint was progression-free survival (PFS) rate at the end of 4 cycles. Secondary objectives included assessment of the safety of RO4929097 and exploration of molecular correlates of outcome in archival tumor tissue and serum.

Results: Of 45 patients enrolled, 40 were evaluable for response. Thirty-seven (82%) patients had high-grade ovarian cancer. No objective responses were observed. Fifteen patients (33%) had stable disease as their best response, with a median duration of 3.1 months. The median PFS for the whole group was 1.3 months (1.2-2.5). Treatment was generally well tolerated with 10% of patients discontinuing treatment due to an adverse event. In high grade serous ovarian cancer patients, the median PFS trended higher when the expression of intracellular Notch (NICD) protein by immunohistochemistry was high versus low (3.3 versus 1.3 months, p=0.09). No clear relationship between circulating angiogenic factors and PFS was found despite a suggestion of an improved outcome with higher baseline VEGFA levels.

Conclusions: RO4929097 has insufficient activity as a single-agent in platinum-resistant ovarian cancer to warrant further study as monotherapy. Future studies are needed to explore the potential for cohort enrichment using NICD expression.
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http://dx.doi.org/10.1016/j.ygyno.2015.03.005DOI Listing
May 2015

B7-H4 expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity.

Cancer Immunol Res 2015 Feb 19;3(2):184-95. Epub 2014 Dec 19.

Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

The B7 family plays a critical role in both positive and negative regulation of immune responses by engaging a variety of receptors on lymphocytes. Importantly, blocking coinhibitory molecules using antibodies specific for CTLA-4 and PD-1 enhances tumor immunity in a subset of patients. Therefore, it is critical to understand the role of different B7 family members since they may be suitable therapeutic targets. B7-H4 is another member that inhibits T-cell function, and it is also upregulated on a variety of tumors and has been proposed to promote tumor growth. Here, we investigate the role of B7-H4 in tumor development and show that B7-H4 expression inhibits tumor growth in two mouse models. Furthermore, we show that B7-H4 expression is required for antitumor immune responses in a mouse model of mammary tumorigenesis. We found that the expression levels of B7-H4 correlate with MHC class I expression in both mouse and human samples. We show that IFNγ upregulates B7-H4 expression on mouse embryo fibroblasts and that the upregulation of B7-H4 on tumors is dependent on T cells. Notably, patients with breast cancer with increased B7-H4 expression show a prolonged time to recurrence. These studies demonstrate a positive role for B7-H4 in promoting antitumor immunity.
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http://dx.doi.org/10.1158/2326-6066.CIR-14-0113DOI Listing
February 2015

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).

Invest New Drugs 2014 Apr 5;32(2):243-9. Epub 2013 May 5.

Princess Margaret Cancer Centre, Drug Development Program, 610 University Avenue, Toronto, Canada, M5G 2M9.

Purpose: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity.

Methods: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg. RO was administered orally, once daily on days 1-3, 8-10, 15-17, 22-24. Gemcitabine was administered at 1,000 mg/m(2) on d1, 8, and 15 in 28 d cycles. Dose limiting toxicities (DLTs) were assessed by CTCAE v4. Serial plasma was collected for RO (total and unbound) and gemcitabine pharmacokinetic analysis. Biomarkers of Notch signaling were assessed by immunohistochemistry in archival tissue. Antitumor activity was evaluated (RECIST 1.1).

Results: A total of 18 patients were enrolled to establish the recommended phase II dose. Of these, 3 patients received 20 mg RO, 7 patients received 30 mg RO, 6 patients received 45 mg RO and 2 patients received 90 mg RO. DLTs were grade 3 transaminitis (30 mg RO), grade 3 transaminitis and maculopapular rash (45 mg RO), and grade 3 transaminitis and failure to receive 75 % of planned RO doses secondary to prolonged neutropenia (90 mg); all were reversible. The maximum tolerated dose was exceeded at 90 mg RO. Pharmacokinetic analysis of both total and free RO confirmed the presence of autoinduction at 45 and 90 mg. Median levels of Notch3 staining were higher in individuals who received fewer than 4 cycles (p = 0.029). Circulating angiogenic factor levels did not correlate with time to progression or ≥ grade 3 adverse events. Best response (RECIST 1.1) was partial response (nasopharyngeal cancer) and stable disease > 4 months was observed in 3 patients (pancreas, tracheal, and breast primary cancers).

Conclusions: RO and gemcitabine can be safely combined. The recommended phase II dose of RO was 30 mg in combination with gemcitabine 1,000 mg/m(2). Although RO exposure was limited by the presence of autoinduction, RO levels achieved exceeded the area under the concentration-time curve for 0-24 h (AUC(0-24)) predicted for efficacy in preclinical models using daily dosing. Evidence of clinical antitumor activity and prolonged stable disease were identified.
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http://dx.doi.org/10.1007/s10637-013-9965-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869895PMC
April 2014

High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer.

Proc Natl Acad Sci U S A 2013 Jan 14;110(5):1714-9. Epub 2013 Jan 14.

Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, ON, Canada M5G 2M9.

Expression of the Notch ligand Jagged 1 (JAG1) and Notch activation promote poor-prognosis in breast cancer. We used high throughput screens to identify elements responsible for Notch activation in this context. Chemical kinase inhibitor and kinase-specific small interfering RNA libraries were screened in a breast cancer cell line engineered to report Notch. Pathway analyses revealed MAPK-ERK signaling to be the predominant JAG1/Notch regulator and this was supported by gene set enrichment analyses in 51 breast cancer cell lines. In accordance with the chemical screen, kinome small interfering RNA high throughput screens identified Tribbles homolog 3 (TRB3), a known regulator of MAPK-ERK, among the most significant hits. We demonstrate that TRB3 is a master regulator of Notch through the MAPK-ERK and TGFβ pathways. Complementary in vitro and in vivo studies underscore the importance of TRB3 for tumor growth. These data demonstrate a dominant role for TRB3 and MAPK-ERK/TGFβ pathways as Notch regulators in breast cancer, establishing TRB3 as a potential therapeutic target.
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http://dx.doi.org/10.1073/pnas.1214014110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562766PMC
January 2013

Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study.

Breast Cancer Res Treat 2012 Oct 30;135(3):821-30. Epub 2012 Aug 30.

Division of Medical Oncology and Hematology, Department of Medicine, Mount Sinai Hospital and Princess Margaret Hospital, University of Toronto, 1284-600 University Avenue, Toronto, ON M5G 1X5, Canada.

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant "window of opportunity" study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13-40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (-0.5 kg/m(2), p < 0.0001), weight (-1.2 kg, p < 0.0001), and HOMA (-0.21, p = 0.047) decreased significantly while non-significant decreases were seen in insulin (-4.7 pmol/L, p = 0.07), leptin (-1.3 ng/mL, p = 0.15) and CRP (-0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.
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http://dx.doi.org/10.1007/s10549-012-2223-1DOI Listing
October 2012

A prospective study of tumor and technical factors associated with positive margins in breast-conservation therapy for nonpalpable malignancy.

Am J Surg 2012 Sep 12;204(3):263-8. Epub 2012 Jul 12.

Department of Surgical Oncology, Princess Margaret Hospital, University Health Network, 610 University Ave., Suite 3-130, Toronto, Ontario, Canada M5G 2M9.

Background: The purpose of this study was to identify factors that predict an increased risk of a positive surgical margin after breast-conserving therapy for nonpalpable carcinoma of the breast.

Methods: In this prospective study, 305 patients with nonpalpable invasive breast cancer or ductal carcinoma in situ were identified and underwent localization lumpectomy. Patient, technical, and tumor factors with a potential to predict margin status were documented.

Results: A 20% positive margin rate was observed. Univariate analysis of patient, tumor, and technical factors revealed that localizations performed under stereotactic guidance (P < .001), presence of in situ disease, high tumor grade, larger tumor size, multifocal disease, and presence of mammographic microcalcifications (P < .02) were predictive of positive margins. With the exception of tumor grade and mammographic microcalcifications, multivariable analysis identified the same factors.

Conclusions: This study identified several factors associated with positive margins that should be considered when planning breast-conserving therapy for nonpalpable tumors.
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http://dx.doi.org/10.1016/j.amjsurg.2012.03.007DOI Listing
September 2012

Notch signaling and breast cancer.

Authors:
Michael Reedijk

Adv Exp Med Biol 2012 ;727:241-57

Department of Surgical Oncology, University Health Network, Ontario, Canada.

It has been more than two decades since Notch has been identified as an oncogene in mouse mammary tumor virus-infected mice. Since this discovery, activated Notch signaling and up-regulation of tumor-promoting Notch target genes have been observed in human breast cancer. In addition, high expression of Notch ligands and receptors has been shown to correlate with poor outcome in this malignancy. Notch affects multiple cellular processes including stem cell maintenance, cell fate specification, differentiation, proliferation, motility and survival. Perturbation of these activities is a hallmark of carcinogenesis and evidence continues to accumulate that aberrant Notch activity influences breast cancer progression through these processes.
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http://dx.doi.org/10.1007/978-1-4614-0899-4_18DOI Listing
April 2012

Developmental pathways in breast cancer and breast tumor-initiating cells: therapeutic implications.

Cancer Lett 2012 Apr 26;317(2):115-26. Epub 2011 Nov 26.

Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, 620 University Avenue, Toronto, Ontario, Canada M5G 2M9.

The recognition of breast cancer as a molecularly heterogeneous disease where individual tumors display cellular hierarchy containing "primitive" stem-like tumor-initiating cells (TICs) and their derivatives, has directed efforts towards the development of personalized targeted therapies based on the characteristics of individual cancers. Targeted therapies are designed to attack processes that uniquely support cancer progression, including maintenance of TICs, invasion, metastasis, cell survival and tumor-related angiogenesis and thereby result in less collateral damage than conventional chemotherapy. Recently, it has been demonstrated that pathways such as Hedgehog (Hh), Wnt and Notch, which regulate development during embryonic life and somatic stem cells (SCs) in the adult organism, can be reactivated in malignancies and support the TIC compartment. Herein, we review the role of developmental pathways in stem cell biology and provide an up-to-date survey of pre-clinical and clinical trials of novel strategies to target them.
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http://dx.doi.org/10.1016/j.canlet.2011.11.028DOI Listing
April 2012

A multicentered, randomized, controlled trial comparing radioguided seed localization to standard wire localization for nonpalpable, invasive and in situ breast carcinomas.

Ann Surg Oncol 2011 Nov 30;18(12):3407-14. Epub 2011 Apr 30.

Department of Surgery, McMaster University, and St. Joseph's Healthcare, Hamilton, ON, Canada.

Background: Studies suggest radioguided seed localization (RSL) yields fewer positive margins than wire-guided localization (WL). The goal of this study is to determine whether RSL is superior to WL.

Methods: Women with confirmed invasive or ductal carcinoma in situ (DCIS) undergoing localization and breast conserving surgery were enrolled. Outcomes measured include positive margin and reoperation rates, specimen weight, operative and localization times, and surgeon and radiologist ranking of procedural difficulty.

Results: Randomization was centralized, concealed, and stratified by surgeon with 153 patients in the WL group and 152 in RSL group. Localizations were performed using either ultrasound (70%) or mammographic guidance (30%). Pathology was either DCIS (18%) or invasive carcinoma (82%). Procedures were performed at 3 sites, by 7 surgeons. Only difference found for patient and tumor characteristics was more multifocal disease in RSL group. Using intention-to-treat analysis, there were no differences in positive margins rates for RSL (10.5%) and WL (11.8%), (P=.99) or for positive or close margins (<1 mm) (RSL 19% and WL 22%; P=.61). Mean operative time (minutes) was shorter for RSL (RSL 19.4 vs WL 22.2; P<.001). Specimen volume, weight, reoperation and localization times were similar. Surgeons ranked the seed technique as easier (P=.008), while radiologists ranked them similarly. Patient's pain rankings during wire localization were higher (P=.038).

Conclusions: In contrast to other trials positive margin and reoperation rates were similar for RSL and WL. However, for RSL operative times were shorter, and the technique was preferred by surgeons, making it an acceptable method for localization.
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http://dx.doi.org/10.1245/s10434-011-1699-yDOI Listing
November 2011

Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer.

Cancer Res 2011 Jan;71(1):277-86

Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Aberrant activation of the Notch receptor signaling pathway and overexpression of the Notch ligand JAG1 are associated with poor outcome in breast cancer. The plasminogen activator system, which includes urokinase-type plasminogen activator (uPA), has been validated as a marker of recurrence, high metastasis risk and death in breast malignancy. By using microarray profiling of breast cancer cell lines that had undergone siRNA-mediated abrogation of Notch signaling we uncovered a link between activated Notch signaling and uPA expression. An association between elevated expression of the Notch ligand JAG1, uPA, and the basal-like breast cancer subtype was confirmed in breast cancer cell lines. The association between JAG1 and uPA expression persisted in a survey of primary carcinomas of the breast. We found that Notch knockdown reduced transcription of uPA and phenocopied uPA knockdown in breast cancer cells. Through mutational analysis we identified a CBF-1 binding site in the uPA promoter that is required for direct transcriptional regulation by Notch. These data suggest that JAG1-induced Notch activation results in breast cancer progression through upregulation of the plasminogen activator system, directly linking these 2 important pathways of poor prognosis.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-2523DOI Listing
January 2011

Expansion and characterization of human melanoma tumor-infiltrating lymphocytes (TILs).

PLoS One 2010 Nov 10;5(11):e13940. Epub 2010 Nov 10.

Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Canada.

Background: Various immunotherapeutic strategies for cancer are aimed at augmenting the T cell response against tumor cells. Adoptive cell therapy (ACT), where T cells are manipulated ex vivo and subsequently re-infused in an autologous manner, has been performed using T cells from various sources. Some of the highest clinical response rates for metastatic melanoma have been reported in trials using tumor-infiltrating lymphocytes (TILs). These protocols still have room for improvement and furthermore are currently only performed at a limited number of institutions. The goal of this work was to develop TILs as a therapeutic product at our institution.

Principal Findings: TILs from 40 melanoma tissue specimens were expanded and characterized. Under optimized culture conditions, 72% of specimens yielded rapidly proliferating TILs as defined as at least one culture reaching ≥3×10(7) TILs within 4 weeks. Flow cytometric analyses showed that cultures were predominantly CD3+ T cells, with highly variable CD4+:CD8+ T cell ratios. In total, 148 independent bulk TIL cultures were assayed for tumor reactivity. Thirty-four percent (50/148) exhibited tumor reactivity based on IFN-γ production and/or cytotoxic activity. Thirteen percent (19/148) showed specific cytotoxic activity but not IFN-γ production and only 1% (2/148) showed specific IFN-γ production but not cytotoxic activity. Further expansion of TILs using a 14-day "rapid expansion protocol" (REP) is required to induce a 500- to 2000-fold expansion of TILs in order to generate sufficient numbers of cells for current ACT protocols. Thirty-eight consecutive test REPs were performed with an average 1865-fold expansion (+/- 1034-fold) after 14 days.

Conclusions: TILs generally expanded efficiently and tumor reactivity could be detected in vitro. These preclinical data from melanoma TILs lay the groundwork for clinical trials of ACT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978109PMC
November 2010

Notch signaling pathway as a therapeutic target in breast cancer.

Mol Cancer Ther 2011 Jan 22;10(1):9-15. Epub 2010 Oct 22.

University of Toronto, Princess Margaret Hospital, 610 University Avenue, Suite 5-222, Toronto, Ontario, M5G 2M9.

The highly conserved Notch signaling pathway is involved in regulating a number of key cellular processes. This pathway has been implicated in both the development and progression of breast cancer and has emerged as a possible therapeutic target. Several clinical trials are currently underway to determine if targeting the Notch pathway with drugs such as the γ-secretase inhibitors may be an effective therapeutic strategy that improves outcomes in this disease.
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http://dx.doi.org/10.1158/1535-7163.MCT-10-0677DOI Listing
January 2011

Mammary ductoscopy in the evaluation and treatment of pathologic nipple discharge: a Canadian experience.

Can J Surg 2009 Dec;52(6):E245-8

Department of Surgical Oncology, Princess Margaret Hospital, Toronto, Ont.

Background: Mammary ductoscopy allows direct visualization of ductal epithelium using a fibreoptic microendoscope. As the first centre in Canada to apply ductoscopy to surgical practice, we report our experience with this technology.

Methods: Between 2004 and 2008, 65 women with pathologic nipple discharge underwent ductoscopy before surgical duct excision under general anesthetic. Prospective data collection included cannulation and complication rates, procedure length and lesion visualization rate compared with preoperative ductography, if performed. In addition, we classified the endoscopic appearance according to Makita and colleagues and correlated it with surgical pathology.

Results: It took longer than 6 months to overcome technical problems before the routine use of ductoscopy in the operating room. The ductoscope was easy to use: we achieved cannulation in 63 of 66 breast ducts (95%) and we visualized a lesion in 52 of 63 breast ducts (83%). The mean procedure length was 5.1 minutes, with no complications. Lesions seen on ductography were seen endoscopically 30 of 33 (91%) times. All 3 malignancies were seen: invasive carcinoma in 1 of 62 (1.6%) and in situ disease in 2 of 62 (3.2%) patients. Surgeons found ductoscopy helpful in defining the extent of duct excision. Except for the "polypoid solitary" class, which accurately predicted a papilloma (23/23), we found poor correlation between Makita and colleague's endoscopic classification and final pathology.

Conclusion: Ductoscopy is feasible, safe and practical. Our surgeons routinely use it to identify the location and extent of duct excision without ordering preoperative ductography. Identifying pathology based on the endoscopic appearance is unreliable unless the lesion is solitary and polypoid.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2792391PMC
December 2009

Cyclin D1 is a direct target of JAG1-mediated Notch signaling in breast cancer.

Breast Cancer Res Treat 2010 Aug 14;123(1):113-24. Epub 2009 Nov 14.

Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Canada.

The Notch ligand, JAG1 is associated with breast cancer recurrence. Herein, we report on a genomics approach to elucidate mechanisms downstream of JAG1 that promote breast cancer growth. In a survey of 46 breast cancer cell lines, we found that triple negative (TN; basal and mesenchymal ER-, PR-, and Her2-negative) lines express JAG1 at significantly higher levels than do HER2(+) or luminal (ER(+)) Her2(-) cell lines. In contrast to the luminal lines tested (T47D and MCF7), TN breast cancer cell lines (HCC1143 and MDA MB231) display high-level JAG1 expression and growth inhibition with RNA interference-induced JAG1 down-regulation. We used microarray profiling of TN tumor cells transfected with JAG1 siRNA to identify JAG1-regulated genes (P or=1.5). Among JAG1-regulated genes identified, cyclin D1 was found to be a direct target of NOTCH1 and NOTCH3. We show that JAG1 down-regulation reduces direct binding of Notch to the cyclin D1 promoter, reduced cyclin D1 expression and inhibition of cell cycle progression through the cyclin D1-dependant G1/S checkpoint. Furthermore, we show that cyclin D1 and JAG1 expression correlate in TN breast cancer expression datasets. These data suggest a model whereby JAG1 promotes cyclin D1-mediated proliferation of TN breast cancers.
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http://dx.doi.org/10.1007/s10549-009-0621-9DOI Listing
August 2010

Activation of Notch signaling in human colon adenocarcinoma.

Int J Oncol 2008 Dec;33(6):1223-9

Program in Developmental Biology and Stem Cell Research, The Hospital for Sick Children, MaRS East Tower, Ontario M5G 1L7, Canada.

Notch and Wnt signaling function together to regulate colonic progenitor cell division and differentiation. Studies in mice have also shown that Notch signaling is required for adenoma formation in response to elevated Wnt-pathway signaling that occurs in the APCMin mouse model of human adenomatous polyposis coli. We therefore used in situ hybridization to analyze expression of Notch ligands, receptors and fringe genes, as well as the Notch target gene, HES1, in human colorectal cancer (CRC). In a small cohort of tumors, JAGGED ligands, NOTCH1, LFNG and HES1 were expressed at levels similar to, or higher than, levels observed in the crypt. To explore the possibility that Notch signaling may play a quantitative role in human CRC we next analyzed HES1 mRNA expression in 130 tumors, each associated with outcome data. The vast majority of these tumors expressed HES1, although at varying levels. Absolute expression levels did not correlate with patient survival. These results establish that JAG ligands and NOTCH1, as well as Notch receptor activation are consistent features of human CRC and support the notion that many of these tumors, like the APCMin mouse, may respond to anti-Notch therapeutic regimes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739737PMC
http://dx.doi.org/10.3892/ijo_00000112DOI Listing
December 2008

Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors.

Breast Cancer Res Treat 2009 Sep 18;117(1):183-91. Epub 2008 Jun 18.

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

Background: BRCA1- and BRCA2-associated tumors appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers.

Methodology: Breast tumor RNAs from 7 BRCA1 and 6 BRCA2 mutation carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors.

Results: Genes more highly expressed in BRCA1-associated tumors included stathmin, osteopontin, TGFbeta2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. BRCA2-associated cancers were characterized by the higher relative expression of FGF1 and FGFR2. FGFR2 protein was also more highly expressed in BRCA2-associated cancers (P = 0.004).

Significance: BRCA1-associated tumours demonstrated increased expression of component genes of the Notch and TGFbeta pathways whereas the higher expression of FGFR2 and FGF1 in BRCA2-associated cancers suggests the existence of an autocrine stimulatory loop.
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http://dx.doi.org/10.1007/s10549-008-0087-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727582PMC
September 2009

Sentinel nodes in breast cancer: relevance of axillary level II nodes and optimal number of nodes that need to be removed.

Ann Surg Oncol 2008 Jun 7;15(6):1710-6. Epub 2008 Mar 7.

Department of Surgical Oncology, Princess Margaret Hospital, University Health Network and University of Toronto, Toronto, Ontario, Canada.

Background: In some patients, the radiocolloid used to perform sentinel lymph node biopsy (SLNB) for breast cancer appears in a number of lymph nodes and in different levels of the axilla. Most positive sentinel lymph node specimens (SLNSs) removed during SLNB are identified in level I of the axilla and within the first 4 SLNSs. Our objective was to verify the staging accuracy of harvesting only the first 4 SLNSs and to determine the relevance of SLNSs that reside in level II of the axilla.

Methods: A prospective database documenting the method of identification, radioisotope count, order of retrieval, and axillary level of SLNSs from 893 SLNBs was analyzed.

Results: A median of 2 SLNSs (range 1-9) were removed per patient. More than 4 SLNSs were found in 8.0%. All SLNSs harboring the largest nodal metastases were identified within the first 4 harvested. Twenty-one percent (184 of 870) of patients had level II SLNSs; 4.9% (9 of 184) were positive. When SLNSs were positive in both levels I and II, the nodal metastases were always of greater or equal size in the level I nodes. Only one patient (0.5%) had a positive level II SLNS macrometastasis (> 2 mm, pN1), with a negative level I SLNS, but it was the hottest node and was removed first.

Conclusions: Removal of more than the first 4 hottest SLNSs does not improve staging accuracy. Level II nodes can be ignored if a hotter level I SLNS is first identified.
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http://dx.doi.org/10.1245/s10434-008-9858-5DOI Listing
June 2008

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

Breast Cancer Res Treat 2008 Oct 8;111(3):439-48. Epub 2007 Nov 8.

Department of Surgical Oncology, University of Toronto, Toronto, ON, Canada, M5G 2M9.

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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http://dx.doi.org/10.1007/s10549-007-9805-3DOI Listing
October 2008

High-level JAG1 mRNA and protein predict poor outcome in breast cancer.

Mod Pathol 2007 Jun;20(6):685-93

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

Notch receptors regulate cell fate determination, stem cell self-renewal, proliferation and apoptosis. We previously reported that elevated mRNA expression of the Notch ligand JAG1 identifies breast cancer patients with a poor prognosis. Here we show through immunohistochemical analysis of the same breast cancer cases (N=127) that patients with tumors expressing high levels of JAG1 protein had a worse outcome than those with tumors expressing low levels (10-year survival 26 vs 48%, and median survival 63 vs 108 months, respectively; P=0.03). We also describe the novel application of the Allred score to quantify JAG1 mRNA and protein expression levels. Using the Allred score, patients with tumors expressing high levels of JAG1 mRNA had a worse outcome than those with tumors expressing low levels (10-year survival 16 vs 47%, and median survival 43 months vs 100 months, respectively; P<0.001). Interestingly, when tumors were classified as either high or low for JAG1 mRNA or protein expression, there was only 65% agreement (kappa=0.08) between the two methods of expression analysis. When JAG1 mRNA and protein data were combined, patients with tumors expressing low levels of both had a 10-year survival of 53% and median survival of 131 months. In comparison, patients with tumors expressing either high levels of JAG1 protein, mRNA or both had reduced 10-year survival and median survival (31%, 19%, 11% and 77, 43, 23 months respectively; P<0.0001). There was marginal evidence of an interaction effect (P=0.055), which indicated that the prognostic value of JAG1 protein was limited to the JAG1 mRNA-low subgroup. These data show that the Allred score can be used to rapidly quantify JAG1 mRNA and protein levels in breast cancer to identify patients who have a significant survival disadvantage and who may benefit from therapies (such as gamma-secretase inhibitors) that target signaling through the Notch pathway.
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http://dx.doi.org/10.1038/modpathol.3800785DOI Listing
June 2007

A case of axillary web syndrome with subcutaneous nodules following axillary surgery.

Breast 2006 Jun 28;15(3):411-3. Epub 2005 Oct 28.

Department of Surgical Oncology, Princess Margaret Hospital, University Health Network and the University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.

Axillary web syndrome (AWS) is a cause of morbidity in the early postoperative period following axillary surgery, which is characterized by cords of subcutaneous tissue extending from the axilla into the medial arm. Few reports have been published describing this entity, which results in pain and a limitation of shoulder abduction. Here, we report a case of AWS that was accompanied with sub-cutaneous nodules mimicking recurrence of breast cancer.
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http://dx.doi.org/10.1016/j.breast.2005.09.005DOI Listing
June 2006

High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival.

Cancer Res 2005 Sep;65(18):8530-7

Program in Developmental Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

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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http://dx.doi.org/10.1158/0008-5472.CAN-05-1069DOI Listing
September 2005