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Background  Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment.    Results  We investigated quantitatively the methylation patterns in the promoter regions of 14 genes ( ABCB1 ,  ATM ,  BRCA1 ,  CDH3 ,  CDKN2A ,  CXCR4 ,  ESR1 ,  FBXW7 ,  FOXC 1,  GSTP1 ,  IGF2 ,  HMLH1 ,  PPP2R2B , and  PTEN ) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters.  Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the  FOXC1  promoter. Absence of methylation at the  ABCB1  promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of  GSTP1 ,  FOXC1  and  ABCB1  correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis  GSTP1  and  FOXC1  methylation status proved to be independent prognostic markers associated with survival.    Conclusions  Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the  ABCB1  or  GSTP1  promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while  FOXC1  methylation might be a protective factor against tumour invasiveness.  FOXC1  proved to be general prognostic factor, while  ABCB1  and  GSTP1  might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions.

molecular cancer

DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response