Promoter methylation status of the FHIT gene and Fhit expression: association with HER2/neu status in breast cancer patients.

Aberrant DNA methylation has been recognized to contribute to breast carcinogenesis, and promoter hypermethylation of several tumor suppressor genes has been correlated with decreased gene expression. The fragile histidine triad (FHIT) gene is a putative tumor suppressor gene in breast and other types of cancer, and loss of Fhit expression has been observed in breast cancer. The aim of the present study was to evaluate the association between methylation of the FHIT gene and its expression in breast cancer, and to investigate whether methylation and expression of the FHIT gene correlates with clinicopathological characteristics in relation to human epidermal growth factor receptor 2 (HER2) status. Pyrosequencing of bisulfite-treated DNA was performed to study the methylation status of the FHIT gene in 60 breast cancer samples. We examined the expression of Fhit using tissue microarrays by immunohistochemical staining. FHIT methylation was detected in 96.7% and the positive expression rate of Fhit was 87.3% of the patients. The mean methylation level of the FHIT gene was associated with intratumoral inflammation. Methylation level of the FHIT gene had no significant differences according to molecular subtypes. Loss of Fhit expression was associated with large tumor size, basal-like subtype and positive expression of EGFR. In HER2-negative breast cancer, loss of Fhit expression was significantly associated with tumor size, estrogen receptor status and Ki-67 proliferation index. No significant correlation between methylation of the FHIT gene and its expression was observed in the present study. Our results suggest that loss of Fhit expression in breast cancer is associated with poor prognostic features, and it is also relevant to the results in HER2-negative breast cancer. Further studies with larger sample sizes and longer follow-up are required to clarify the predictive and prognostic value of Fhit expression and the FHIT gene methylation status in breast cancer.