DNA hypermethylation of PITX2 is a marker of poor prognosis in untreated lymph node-negative hormone receptor-positive breast cancer patients

Breast Cancer Res Treat. 2008 Oct;111(3):429-37. doi: 10.1007/s10549-007-9800-8. Epub 2007 Oct 28.

Abstract

Background: In this study, we evaluated if PITX2 DNA methylation is a marker for disease recurrence in lymph node-negative (LNN), steroid hormone receptor-positive (HR+) breast cancer patients. In addition, we studied the association between PITX2 DNA methylation and PITX2 gene expression.

Patients and methods: PITX2 DNA-methylation was measured in tumor tissue from 412 LNN/HR+ breast cancer patients who had not received any adjuvant systemic treatment. In addition, PITX2 DNA-methylation and mRNA expression was evaluated in 32 breast cancer cell lines.

Results: In univariate Cox regression analysis, DNA-methylation of PITX2 as a continuous variable was associated with early distant metastasis (HR = 1.71; P < 0.01) and poor overall survival (HR = 1.71; P < 0.01). In multivariate analysis together with the established prognostic factors age, tumor size and tumor grade, and steroid hormone receptor levels, both associations retained their significance (for MFS, HR = 1.74; P < 0.01; for OS, HR = 1.46; P = 0.02). In the breast cancer cell lines, PITX2 DNA methylation was inversely association with PITX2A and PITX2B mRNA expression (P < 0.01).

Conclusions: Hypermethylation of PITX2 is, in cell lines, negatively associated with PITX2 mRNA expression and, in clinical specimens, positively associated with breast cancer disease progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / surgery
  • Cell Line, Tumor
  • DNA Methylation*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Lymph Nodes / pathology
  • Middle Aged
  • Neoplasm Metastasis
  • Prognosis
  • RNA, Messenger / analysis
  • Receptors, Steroid / analysis
  • Retrospective Studies
  • Survival Analysis
  • Time Factors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Biomarkers, Tumor
  • Homeodomain Proteins
  • RNA, Messenger
  • Receptors, Steroid
  • Transcription Factors
  • homeobox protein PITX2