Purpose: Aberrant DNA methylation has been recognized to contribute to breast carcinogenesis, and promoter hypermethylation of many 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 cancers, and loss of Fhit expression has been observed in breast cancers. The aim of this 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 would correlate with clinicopathological characteristics in relation to human epidermal growth factor receptor 2 (HER2) status.

Methods: Pyrosequencing of bisulfite treated DNA was performed to study the methylation status of the FHIT gene in 60 breast cancer samples from Korean women obtained at Daegu Catholic University Hospital. We examined the expression of FHIT using tissue microarrays by immunohistochemical staining. Association between the methylation status of the FHIT gene and its expression was analyzed, and the relationship between the FHIT expression and the clinicopathological characteristics of the patients was evaluated.

Results: FHIT methylation was detected in 96.7% and 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 cancers, loss of Fhit expression was significantly associated with tumor size, estrogen receptor status and Ki-67 proliferation index. There was no significant correlation between methylation of the FHIT gene and its expression in this study.

Conslusion: Our study revealed that loss of Fhit expression in breast cancer is associated with poor prognostic features, although there is no significance association between the FHIT gene methylation and Fhit expression. We found that in HER2-negatvie breast cancers, loss of Fhit expression was associated with poor prognostic features. These results support the possibility of potential complementation between HER2 and the Fhit pathway. The clinical significance of our findings needs to be further evaluated in larger cohorts with longer follow-up.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-06-05.