Research Papers:
Differential involvement of RASSF2 hypermethylation in breast cancer subtypes and their prognosis
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Abstract
Noemi Perez-Janices1,2, Idoia Blanco-Luquin1,2,3, Natalia Torrea4, Therese Liechtenstein2,4, David Escors2,4, Alicia Cordoba5, Francisco Vicente-Garcia6, Isabel Jauregui5, Susana De La Cruz7, José Juan Illarramendi7, Valle Coca8, Maria Berdasco9, Grazyna Kochan4, Berta Ibañez10, José Miguel Lera6, David Guerrero-Setas1
1Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet (FMS), Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Navarra, Spain
2Division of Infection and Immunity, Rayne Institute, University College London (UCL), London, United Kingdom
3Cancer Immunomodulation Group, Navarrabiomed-Fundacion Miguel Servet, IdiSNA, Navarra, Spain
4Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom
5Department of Pathology, Complejo Hospitalario de Navarra, Navarra Health Service, Pamplona, Navarra, Spain
6Department of Surgery, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain
7Department of Medical Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain
8Biobank Unit, Navarrabiomed-Fundacion Miguel Servet, IdiSNA, Navarra, Spain
9Cancer Epigenetics Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
10Red de Evaluación en Servicios Sanitarios y Enfermedades Cronicas (REDISSEC), Navarrabiomed-Fundación Miguel Servet, IdiSNA, Navarra, Spain
Correspondence to:
David Guerrero-Setas, e-mail: [email protected]
Keywords: breast cancer, DNA methylation, prognosis, RASSF1, RASSF2
Received: January 09, 2015 Accepted: May 22, 2015 Published: June 04, 2015
ABSTRACT
Breast cancer is a heterogeneous disease that can be subdivided into clinical, histopathological and molecular subtypes (luminal A-like, luminal B-like/HER2-negative, luminal B-like/HER2-positive, HER2-positive, and triple-negative). The study of new molecular factors is essential to obtain further insights into the mechanisms involved in the tumorigenesis of each tumor subtype. RASSF2 is a gene that is hypermethylated in breast cancer and whose clinical value has not been previously studied. The hypermethylation of RASSF1 and RASSF2 genes was analyzed in 198 breast tumors of different subtypes. The effect of the demethylating agent 5-aza-2′-deoxycytidine in the re-expression of these genes was examined in triple-negative (BT-549), HER2 (SK-BR-3), and luminal cells (T-47D). Different patterns of RASSF2 expression for distinct tumor subtypes were detected by immunohistochemistry. RASSF2 hypermethylation was much more frequent in luminal subtypes than in non-luminal tumors (p = 0.001). The re-expression of this gene by lentiviral transduction contributed to the differential cell proliferation and response to antineoplastic drugs observed in luminal compared with triple-negative cell lines. RASSF2 hypermethylation is associated with better prognosis in multivariate statistical analysis (P = 0.039). In conclusion, RASSF2 gene is differently methylated in luminal and non-luminal tumors and is a promising suppressor gene with clinical involvement in breast cancer.
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