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Clinicopathological Significance of Fragile Histidine Triad Transcription Protein Expression in Breast Carcinoma¹

Department of General Surgery, Affiliated Kihoku Hospital, Wakayama Medical University, 649-7113 Katuragi-cho, Japan [Q. Y., G. Y., T. Su., T. T., T. U., T. Sa.]; Second Department of Pathology, Wakayama Medical College, 641-0012 Wakayama City, Japan [Q. Y., M. N., Y. N., I. M., K. K.]; and Department of General Surgery, Qilu Hospital, Shandong University, Ji’nan, Shandong Province, People’s Republic of China [Q. Y.]

The fragile histidine triad (Fhit) gene, which is frequently lost in many cancers, was identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. Loss of Fhit expression is an important step in tumor progression from premalignancy, to in situ, to invasive breast carcinoma. To determine whether the absence of Fhit protein correlates with other established pathological-clinical parameters or prognosis, we assessed Fhit expression using immunohistochemistry in 166 invasive breast carcinomas. Lost or significantly decreased Fhit protein expression was identified in 70 cases (42.2%). Fhit expression was inversely correlated with histological grade (P < 0.0001), negative estrogen receptor status (P = 0.0016), p53 overexpression (P = 0.0040), and tumor proliferation activity (P = 0.0006). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that reduced expression of Fhit was associated with a poor outcome (P = 0.0086, by log-rank test). Multivariate analysis using the stepwise Cox proportional hazard model showed that lymph node metastasis was related to poor survival rates; in addition, patients with loss of Fhit expression still tended to have poor survival (P = 0.0563). Therefore, loss of Fhit expression is associated with higher malignant phenotypes and appears to be a prognostic factor in breast carcinoma.

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