Karoline Berger1, Sara Rhost1, Svanheiður Rafnsdóttir1,2, Éamon Hughes1, Ylva Magnusson1, Maria Ekholm3,4,5, Olle Stål3,4, Lisa Rydén5, Göran Landberg6. 1. Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden. 2. Present address: Department of Surgery, National University Hospital of Iceland, 13-A Hringbraut, Reykjavik, Iceland. 3. Department of Oncology, Region Jönköping County, Jönköping, Sweden. 4. Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. 5. Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden. 6. Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Box 425, Medicinaregatan 1G, SE-13 90, Gothenburg, Sweden. goran.landberg@gu.se.
Abstract
BACKGROUND: The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients. METHODS: We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers. RESULTS: Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance. CONCLUSION: Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.
BACKGROUND: The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancerpatients. METHODS: We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancerpatients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers. RESULTS: Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance. CONCLUSION: Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.
Entities:
Keywords:
Biomarker; Breast cancer; Cancer stem cells; Estrogen receptor; Predictive; Prognostic; Progranulin; Sortilin; Tamoxifen; Targeted therapy
Authors: Tenna Juul Schrøder; Søren Christensen; Samsa Lindberg; Morten Langgård; Laurent David; Philip J Maltas; Jørgen Eskildsen; Jan Jacobsen; Lena Tagmose; Klaus Bæk Simonsen; Lars Christian Biilmann Rønn; Inge E M de Jong; Ibrahim J Malik; Jens-Jakob Karlsson; Christoffer Bundgaard; Jan Egebjerg; Jeffrey B Stavenhagen; Dorthe Strandbygård; Søren Thirup; Jacob Lauwring Andersen; Srinivas Uppalanchi; Sridhar Pervaram; Shiva Prasad Kasturi; Pradheep Eradi; Durga Rao Sakumudi; Stephen P Watson Journal: Bioorg Med Chem Lett Date: 2013-11-27 Impact factor: 2.823
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