The Significance Of KLF4 Expression And Prognosis In The Breast Invasive Ductal Carcinoma Tissue

Objective:Breast cancer is the most common malignant tumor of women worldwide. Although the incidence of female breast cancer in China was lower than the global level, but the incidence rate is of rapid growth in recent years. According to the national report, there were nearly 210000 women were diagnosed as breast cancer patients every year. The incidence has become the first of female cancer. There were 45,000 female’s death dued to breast cancer every year, ranked the sixth cause of cancer death in women. 90% of the patients died in clinic are due to the recurrence and metastasis of breast cancer. So far, it has been recognized that, tumor is a complex disease which is accumulated much changes of multi factors, multi genes and multi stage. Oncogenes and tumor suppressor genes play an important role in many significant processes by regulating different downstream target genes, such as cell growth, death and metabolism, and so on. Once these genes are abnormal, it will affect the signal of transduction network, disrupt cell growth, death and metabolic process, leading to carcinogenesis. Therefore, looking for gene target in the process of development in tumor has become a hot focus in cancer prevention and control in recent years.Krüppel-like factor 4（KLF4） is a zinc-finger transcription factor that regulates many essential processes, including development and cell differentiation, proliferation, and apoptosis. Along with these roles in normal cells and tissues, KLF4 has important tumor suppressive or oncogenic two-way functions in most malignancies. Some studies have confirmed that the expression of KLF4 in human solid tumors is significantly associated with the genesis, development and prognosis of different tumors. However, the precise role of KLF4 in breast invasive ductal carcinoma remains unclear. The expression of KLF4 in breast invasive ductal carcinoma tissue and normal mammary duct epithelium tissue were detected to investigate the relation among KLF4 level and the clinicopathological features and prognosis in the breast cancer. It is expected that a potential new therapeutic target for the treatment for breast cancer would be found.Methods:1 This research’s object was randomly recruited 126 surgical resection cases with primary breast invasive ductal carcinoma paraffin embedded tissue from January to December 2008 at breast cancer center of the Fourth Hospital of Hebei Medical University which also had complete follow-up data. 10 cases of normal mammary duct epithelium tissue in the same period were compared as the control group. The expression of KLF4 in breast invasive ductal carcinoma tissue and normal mammary duct epithelium tissue was detected by Max Vision^TM One Step immunohistochemical stain.2 To compare the difference of the expression of breast invasive ductal carcinoma and normal mammary duct epithelium tissue between the two groups KLF4.Then KLF4 level was compared with the clinicopathological features and follow-up datas of breast cancer, such as tumor size, pathological grade, vessel tumor embolus and the level of ER, PR, HER-2 and Ki-67, DFS, OS, to investigate the correlation between KLF4 expression and clinicopathological features and prognosis of breast invasive ductal carcinoma.3 Statistical analyses were performed by SPSS 19.0 software. The results of immunohistochemical stain were analyzed using Chi-square test and Spearman order correlated examination. The Kaplan-Meier survival curve was analyzed by univariate survival analysis, and the COX regression model was used for multivariate survival analysis. All statistical tests were considered significant at P<0.05.Results:1 In the 126 cases of breast invasive ductal carcinoma specimens, 65 cases displayed low expression of KLF4, while 61 cases displayed high expression of KLF4. In the 10 cases of normal mammary duct epithelium tissue specimens, 1 cases displayed low expression, while 61 cases displayed high expression of KLF4. The low expression of KLF4 in breast invasive ductal carcinoma was higher than that of the low expression rate in normal mammary duct epithelium tissue（51.6% vs 10%）, with χ²=4.848 and P=0.028,The expression difference was of statistical significance.2 According to the tumor size of breast cancer, 126 patients were divided into ≤2cm group, a total of 59 cases, including 24 cases of patients with low expression of KLF4（24/59,40.68%）;>2cm 且≤5cm group, a total of 62 cases, including 37 cases of patients with low expression of KLF4（37/62,59.68%）;>5cm group, a total of 5 cases,including 4 cases of patients with low expression of KLF4（4/5,80%）; the expression difference was of statistical significance, with χ²=6.053 and P=0.048. The expression of KLF4 was negatively correlated with the size of primary tumor.3 According to the number of lymph node metastasis after surgery, 126 patients were divided into N0（no lymph node metastasis） group, a total of 80 cases; N1（1³ lymph node metastasis） group, a total of 29 cases; N2（4⁹ lymph node metastasis） group, a total of 10 cases; N3（over 10 lymph node metastasis） group, a total of 7 cases.The four group of KLF4 low expression rate respectively 36.3%,75.9%,80%,87.5%. The expression difference was of statistical significance, with χ²=20.874 and P<0.001. The expression of KLF4 was significantly negatively correlated with the size of primary tumor.4 The 126 cases with primary breast cancer were divided into 3 groups according to clinical stage, stage Ⅰ group with 39 cases（30.9%）, stage Ⅱ group with 49 cases（38.9%） and stage group with Ⅲ 38 cases（30.2%）. The expression difference of KLF4 in above three groups was of statistical significance, with χ²=43.298 and P < 0.001. KLF4 expression was significantly negatively correlated with the clinical stage of primary breast cancer.5 The cases with primary breast cancer were divided into 2 groups according to the status of vessel tumor embolus, tumor embolus group with 51 cases and non-tumor embolus group with 75 cases. The expression difference of KLF4 between above two groups was of statistical significance, with χ²=5.251 and P=0.029.6 According to the status of ER, the cases with primary breast cancer were divided into 2 groups:ER（+）group, a total of 89 cases, including 52 cases of patients with low expression of KLF4; ER（-）group, a total of 80 cases, including 13 cases of patients with low expression of KLF4. The two group of KLF4 low expression rate respectively 58.4%（52/89） vs 35.1%（13/37）. The expression difference of KLF4 between two groups was of statistical significance, with χ²=4.783 and P=0.021.7 According to the patients during follow-up have experienced adverse events such as the case of recurrence and metastasis, the cases with breast cancer were divided into 2 groups:non recurrence and metastasis group,a total of 85 cases; recurrence and metastasis group,a total of 41 cases.The expression difference of KLF4 between two groups was of statistical significance, with χ²=14.043 and P<0.001.8 According to the the survival situation by the end of follow-up, the cases with breast cancer were divided into 2 groups:living group and dead group, the low expression of KLF4 in the two groups respectively 44.3% and 75.9%,the expression difference of KLF4 between two groups was of statistical significance, with χ²=8.888 and P=0.003.9 The expression of KLF4 was not associated with the age of patient, different subtypes of breast cancer, Histological grade and the expression of PR, HER-2, P53 and Ki-67, with P>0.05.10 The high expression of KLF4 group five years survival rate is higher than that of KLF4 low,repectly 90.2%,76.9%, the difference was of statistical significance, with χ²=3.972 and P=0.046. This suggests that low expression of KLF4 means poor prognosis.The univariate analysis of Kaplan-Meier survival curve showes that the expression of KLF4 is negatively associated with DFS and OS in breast cancer patients.The high expression of KLF4 group was significantly higher than the survival of the low.11 Cox’s multivariate regression analysis model shows that the lymph node metastasis is a independent prognostic risk factor of disease-free survival in breast cancer patients,with P=0.004, RR=1.569. While lymph node metastasis（ P=0.001） and recurrence or metastas（ P=0.007） are two independent risk factors for significant effects of overall survival in breast cancer patients, respectly RR=1.698 and RR=526.870.Conclusions:1 The expression of KLF4 in breast invasive ductal carcinoma tissue than that in normal mammary duct epithelium tissue decreased, suggesting that KLF4 may be a potential tumor suppressor gene in the breast cancer.2 The expression of KLF4 in the larger diameter of tumor,more lymph node metastasis, higher TNM clinical stage,existing vessel tumor embolus, ER（-）, emergence of recurrence and metastasis in breast invasive ductal carcinoma tissue were lower expression, suggesting that KLF4 expression is negatively related to the malignant degree of tumor in breast invasive ductal carcinoma.3 The expression of KLF4 was negatively correlated with DFS and OS in the breast cancer patients which is suggesting that the lower expression of KLF4 in breast invasive ductal carcinoma is associated with the poorer prognosis, but it can not be a independent factors affecting the prognosis of breast cancer.