Aberrant Keap1 methylation in breast cancer and association with clinicopathological features

Raffaela Barbano, Lucia Anna Muscarella, Barbara Pasculli, Vanna Maria Valori, Andrea Fontana, Michelina Coco, Annamaria la Torre, Teresa Balsamo, Maria Luana Poeta, Giovanni Francesco Marangi, Evaristo Maiello, Marina Castelvetere, Fabio Pellegrini, Roberto Murgo, Vito Michele Fazio, Paola Parrella

Research output: Contribution to journalArticlepeer-review

Abstract

Keap1 (Kelch-like ECH -associated protein 1) is an adaptor protein that mediates the ubiquitination/degradation of genes regulating cell survival and apoptosis under oxidative stress conditions. We determined methylation status of the KEAP1 promoter in 102 primary breast cancers, 14 pre-invasive lesions, 38 paired normal breast tissues and 6 normal breast from reductive mammoplasty by quantitative methylation specific PC R (QMSP). Aberrant promoter methylation was detected in 52 out of the 102 primary breast cancer cases (51%) and 10 out of 14 pre-invasive lesions (71%). No mutations of the KEAP1 gene were identified in the 20 breast cancer cases analyzed by fluorescence based direct sequencing. Methylation was more frequent in the subgroup of patients identified as ER positive-HER2 negative tumors (66.7%) as compared with triple-negative breast cancers (35%) (p = 0.05, Chi-square test). The impact of the interactions between Er, PgR, Her2 expression and KEAP1 methylation on mortality was investigated by RECPA M multivariable statistical analysis, identifying four prognostic classes at different mortality risks. Triple-negative breast cancer patients with KEAP1 methylation had higher mortality risk than patients without triple-negative breast cancer (HR = 14.73, 95% CI: 3.65-59.37). Both univariable and multivariable COX regressions analyses showed that KEAP1 methylation was associated with a better progression free survival in patients treated with epirubicin/cyclophosfamide and docetaxel as sequential chemotherapy (HR = 0.082; 95% CI: 0.007-0.934). These results indicate that aberrant promoter methylation of the KEAP1 gene is involved in breast cancerogenesis. In addition, identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction in breast cancer patients.

Original languageEnglish
Pages (from-to)105-112
Number of pages8
JournalEpigenetics
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 2013

Keywords

  • Breast cancer
  • Estrogen
  • KEAP1
  • Methylation
  • Oxidative stress
  • Prognosis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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