Abstract 664: Aberrant KEAP1 promoter methylation is associated with disease progression in breast cancer patients treated with epirubicin/cyclophosfamide and docetaxel chemotherapy.
Authors: Barbano Raffaela , Muscarella Lucia Anna , Pasculli Barbara , Valori Vanna Maria , Fontana Andrea , Coco Michelina , la Torre Annamaria , Balsamo Teresa , Poeta Maria Luana , Marangi Giovanni Francesco , Maiello Evaristo , Castelvetere Marina , Pellegrini Fabio , Murgo Roberto , Fazio Vito Michele , Parrella Paola 
Published: August 2014

Abstract
The 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 investigated the possible contribution of KEAP1 genetic and epigenetic abnormalities to development and progression of breast cancer. Methylation status of the KEAP1 promoter was evaluated 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 PCR (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=0.02, Mann Whitney U-test). Interactions between ER, PR, HER2 expression and KEAP1 methylation on the mortality were investigated by RECPAM 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 regression 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=0.096; 95%CI: 0.011-0.832 p=0.03 and HR=0.082 95%CI: 0.007-0.934 P=0.04 respectively). Our data indicate that aberrant promoter methylation of the KEAP1 gene promoter is involved in breast cancerogenesis. In addition identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction in breast cancer patients.
Citation Format: 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. Aberrant KEAP1 promoter methylation is associated with disease progression in breast cancer patients treated with epirubicin/cyclophosfamide and docetaxel chemotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 664. doi:10.1158/1538-7445.AM2013-664