Differential involvement of RASSF2 hypermethylation in breast cancer subtypes and their prognosis.
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.
Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet (FMS), Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Navarra, Spain.|Division of Infection and Immunity, Rayne Institute, University College London (UCL), London, United Kingdom.
Noemi
N
Perez-Janices
Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet (FMS), Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Navarra, Spain.|Division of Infection and Immunity, Rayne Institute, University College London (UCL), London, United Kingdom.|Cancer Immunomodulation Group, Navarrabiomed-Fundacion Miguel Servet, IdiSNA, Navarra, Spain.
Idoia
I
Blanco-Luquin
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
Natalia
N
Torrea
Division of Infection and Immunity, Rayne Institute, University College London (UCL), London, United Kingdom.|Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
Therese
T
Liechtenstein
Division of Infection and Immunity, Rayne Institute, University College London (UCL), London, United Kingdom.|Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
David
D
Escors
Department of Pathology, Complejo Hospitalario de Navarra, Navarra Health Service, Pamplona, Navarra, Spain.
Alicia
A
Cordoba
Department of Surgery, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain.
Francisco
F
Vicente-Garcia
Department of Pathology, Complejo Hospitalario de Navarra, Navarra Health Service, Pamplona, Navarra, Spain.
Isabel
I
Jauregui
Department of Medical Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain.
Susana
S
De La Cruz
Department of Medical Oncology, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain.
José Juan
JJ
Illarramendi
Biobank Unit, Navarrabiomed-Fundacion Miguel Servet, IdiSNA, Navarra, Spain.
Valle
V
Coca
Cancer Epigenetics Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
Maria
M
Berdasco
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom.
Grazyna
G
Kochan
Red de Evaluación en Servicios Sanitarios y Enfermedades Cronicas (REDISSEC), Navarrabiomed-Fundación Miguel Servet, IdiSNA, Navarra, Spain.
Berta
B
Ibañez
Department of Surgery, Complejo Hospitalario de Navarra, Navarra Health Service, Navarra, Spain.
José Miguel
JM
Lera
Cancer Epigenetics Group, Navarrabiomed-Fundación Miguel Servet (FMS), Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, Navarra, Spain.
David
D
Guerrero-Setas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000737:chemistry; D001374:Azacitidine / Q000737:chemistry; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; C411762:RASSF1 protein, human; C425300:RASSF2 protein, human; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; D001374:Azacitidine
DNA methylation; RASSF1; RASSF2; breast cancer; prognosis