Research Papers:

Differential expression of neurogenes among breast cancer subtypes identifies high risk patients

Patricia Fernández-Nogueira, Paloma Bragado, Vanessa Almendro, Elisabet Ametller, Jose Rios, Sibgat Choudhury, Mario Mancino _ and Pedro Gascón

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Oncotarget. 2016; 7:5313-5326. https://doi.org/10.18632/oncotarget.6543

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Patricia Fernández-Nogueira1,3, Paloma Bragado1, Vanessa Almendro4, Elisabet Ametller1,2, Jose Rios5,6, Sibgat Choudhury4, Mario Mancino1,2,*, Pedro Gascón1,2,3,*

1Department of Medical Oncology, Hospital Clínic, Barcelona, Spain

2Institut d’Investigacions Biomediques August Pi i Sunyer Barcelona, Barcelona, Spain

3Department of Medicine, University of Barcelona, Barcelona, Spain

4Division of Medical Oncology, Department of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA, USA

5Medical Statistics Core Facility, IDIBAPS, (Hospital Clinic) Barcelona, Barcelona, Spain

6Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

*These authors have contributed equally to this work

Correspondence to:

Mario Mancino, e-mail: [email protected]

Pedro Gascón, e-mail: [email protected]

Keywords: breast cancer, neurogenes, neuropeptides, neurotransmitters, tumor microenvironment

Received: September 01, 2015     Accepted: November 22, 2015     Published: December 10, 2015


The nervous system is now recognized to be a relevant component of the tumor microenvironment. Receptors for neuropeptides and neurotransmitters have been identified in breast cancer. However, very little is known about the role of neurogenes in regulating breast cancer progression. Our purpose was to identify neurogenes associated with breast cancer tumorigenesis with a potential to be used as biomarker and/or targets for treatment. We used three databases of human genes: GeneGo, GeneCards and Eugenes to generate a list of 1266 relevant neurogenes. Then we used bioinformatics tools to interrogate two published breast cancer databases SAGE and MicMa (n=96) and generated a list of 7 neurogenes that are differentially express among breast cancer subtypes. The clinical potential was further investigated using the GOBO database (n=1881). We identified 6 neurogenes that are differentially expressed among breast cancer subtypes and whose expression correlates with prognosis. Histamine receptor1 (HRH1), neuropilin2 (NRP2), ephrin-B1 (EFNB1), neural growth factor receptor (NGFR) and amyloid precursor protein (APP) were differentially overexpressed in basal and HER2-enriched tumor samples and syntaxin 1A (STX1A) was overexpressed in HER2-enriched and luminal B tumors. Analysis of HRH1, NRP2, and STX1A expression using the GOBO database showed that their expression significantly correlated with a shorter overall survival (p < 0.0001) and distant metastasis-free survival (p < 0.0001). In contrast, elevated co-expression of NGFR, EFNB1 and APP was associated with longer overall (p < 0.0001) and metastasis-free survival (p < 0.0001). We propose that HRH1, NRP2, and STX1A can be used as prognostic biomarkers and therapeutic targets for basal and HER2-enriched breast cancer subtypes.

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