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

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.

• Authors: Inko Nimmrich, Anieta M Sieuwerts, Marion E Meijer-van Gelder, Ina Schwope, Joan Bolt-de Vries, Nadia Harbeck, Thomas Koenig, Oliver Hartmann, Antje Kluth, Dimo Dietrich, Viktor Magdolen, Henk Portengen, Maxime P Look, Jan G M Klijn, Ralf Lesche, Manfred Schmitt, Sabine Maier, John A Foekens, John W M Martens
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 111 Issue 3 Pg. 429-37 (Oct 2008) ISSN: 0167-6806 [Print] Netherlands
• PMID: 17965955 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Aged
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism, mortality, pathology, surgery)
• Cell Line, Tumor
• DNA Methylation
• Female
• Gene Expression Regulation, Neoplastic
• Homeodomain Proteins (genetics, 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, metabolism)
• Homeobox Protein PITX2