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Original article
TP73 DNA methylation and upregulation of ΔNp73 are associated with an adverse prognosis in breast cancer
  1. Laura C Gomez1,2,
  2. Mayra L Sottile1,
  3. Martin E Guerrero-Gimenez3,4,
  4. Felipe C M Zoppino3,4,
  5. Analia L Redondo1,4,
  6. Francisco E Gago5,
  7. Javier I Orozco4,5,6,
  8. Olga M Tello5,
  9. Maria Roqué2,7,
  10. Silvina B Nadin1,
  11. Diego M Marzese6,
  12. Laura M Vargas-Roig1,4
  1. 1 Tumor Biology Laboratory, Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Scientific and Technical Research Council (CONICET), Mendoza, Argentina
  2. 2 Faculty of Exact Sciences, National University of Cuyo, Mendoza, Argentina
  3. 3 Oncology Laboratory, IMBECU-CONICET, Mendoza, Argentina
  4. 4 Medical School, National University of Cuyo, Mendoza, Argentina
  5. 5 Gineco-Mamario Institute, San Lorenzo, Mendoza, Argentina
  6. 6 Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, USA
  7. 7 IHEM-CONICET, Mendoza, Argentina
  1. Correspondence to Diego M Marzese, Department of Translational Molecular Medicine, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, USA; marzesed{at}jwci.org and Dr Laura M Vargas-Roig, Institute of Medicine and Experimental Biology of Cuyo, C.C. 855, Mendoza 5500, Argentina; vargasl{at}mendoza-conicet.gob.ar

Abstract

Aim Accumulated evidence suggests that aberrant methylation of the TP73 gene and increased levels of ΔNp73 in primary tumours correlate with poor prognosis. However, little is known regarding the transcriptional and functional regulation of the TP73 gene in breast cancer. The aim of the present study was to determine the expression of the ΔNp73 isoform, its relationship with DNA methylation of TP73 and their clinical prognostic significance in breast cancer patients.

Methods TP73 gene methylation was studied in TCGA datasets and in 70 invasive ductal breast carcinomas (IDCs). The expression of p73 isoforms was evaluated by immunohistochemistry (IHC) and Western blot and correlated with clinicopathological variables and clinical outcome.

Results We observed that the methylation of diverse CpG islands of TP73 differed significantly between molecular subtypes. An inverse correlation was found between p73 protein expression and the methylation status of the TP73 gene. The expression of exon 3’ of p73 (only expressed in ΔNp73) was significantly higher in patients with wild-type p53. Immunohistochemical analysis revealed that all p73 isoforms were localised in both the nuclear and cytoplasmic compartments. We confirmed a positive association between the expression of ∆Np73 and high histological grade.

Conclusions Our findings suggest that high expression of ΔNp73 could be used to determine the aggressiveness of IDCs and could be incorporated in the pathologist’s report.

  • BREAST CANCER
  • DIAGNOSTICS
  • MOLECULAR PATHOLOGY
  • DNA

https://doi.org/10.1136/jclinpath-2017-204499

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    Footnotes

    • DMM and LMV-R contributed equally.

    • Handling editor Runjan Chetty.

    • Contributors LCG, FEG, JIO, OMT, DMM and LMV-R contributed to the conception and design of the work. LCG, MLS, MEG-G, FCMZ and AR performed the analysis and interpreted the results. MR and SBN assisted in editing the manuscript. LCG, MLS, DMM and LMV-R contributed to the analysis of the data and wrote the manuscript.

    • Funding This work was supported by the National Cancer Institute, Ministry of Health of Argentina (LMV-R), CONICET, Argentina Grant: PIP 27913 (LMV-R), and National University of Cuyo, Argentina Grant: 06-J463 (LMV-R); the Associates for Breast and Prostate Cancer Studies (ABCs) (Grant ID: 887377001-40000) award (DM and JIO) and the Fashion Footwear Association of New York (FFANY) (Grant ID: 88737700160000) foundation (DMM).

    • Competing interests None declared.

    • Ethics approval Ethics Committee of the Medical School, National University of Cuyo, Mendoza, Argentina.

    • Provenance and peer review Not commissioned; externally peer reviewed.