Expression And Significance Of HIF-1α, P-gp And Topo-Ⅱα In Breast Cancer

Background and Objective: Breast cancer is the most common malignant disease of women. Recently, the mortality of breast cancer is sharp rising in China, especially in big citys. Breast cancer has already been regarded as a systemic disease, and chemotherapy is one of the important therapeutic approaches to treat breast cancer. But the disease free survival (DFS) of patients has been induced by the appearance of drug resistant, so it is important to probe the breast cancer resistant related gene and guide the standard therapeutics. The relationship between the changes of cell microenvironment and multidrug resistance (MDR) becomes a new hot spot. The most important change of cell microenvironment is the ischemia and hypoxia. Since hypoxia-inducible factor-1 (HIF-1) plays an important role in cell microenvironment changes,it is very interesting to investigate the relationship between MDR and HIF-1α—the active subunit of HIF-1. The over expression of permeability-glycoprotein (P-gp) plays a more important role in MDR, The DNA topoisomerase-Ⅱ(Topo-Ⅱ) is the effective target of many anti-tumor medicine including anthracycline, and it is often associated with drug resistance when its level decrease. This study was designed to evaluate the expression of HIF-1αand P-gp, Topo-Ⅱαin breast cancer by immunohistochemistry and investigate the relationships between their expressions and the clinicopathological characteristics, and we also analysed the association among their expressions,which may reveal the role of hypoxia in the pathogenesis and progression of breast cancer. Thus we would find a promising target for therapy and a potentially useful factor for prognostic detection in breast cancer,which would retroconverse tumor drug resistance and improve the effect of chemotherapy.Methods: We collected 59 breast cancer samples which were resected by surgery and confirmed by pathology in the First Hospital of Qin Huangdao from September, 2000 to December, 2003. We detected the expression of HIF-1α, P-gp and Topo-Ⅱαusing immunohistochemieal SP methods to investigate the relationship between them,as well as the correlate with clinicopathological characteristics in human breast cancer. Statistical methodsχ2 test was performed by SPSS software version 14.0.Results: 1 Expression of HIF-1α, P-gp and Topo-Ⅱαin breast cancer: The positive rates of the expression of HIF-1α, P-gp and Topo-Ⅱαin 59 cases were 61.01%,40.68% and 49.15% respectively. These proteins were all negative in 15 normal breast tissues. And there were significant differences between breast cancer tissues and normal tissues (P<0.05).2 The relationship of the expression of HIF-1α, P-gp and Topo-Ⅱαand the clinicopathological characteristics:Expression of HIF-1αwas positively related to tumor size, histological gradesand and lymph node matastasis, and had linear trend with tumor size and histological grades (P<0.05). And it was not correlated with patients'age, pTNM stages, histological types and menstruation status (P>0.05).The positive rate of the expression of P-gp in lymph node matastasis group (52.94%) was higher than that in no lymph node matastasis group (24.00%), the difference had statistical significance (P<0.05). The expression of P-gp had significantly positive correlation with lymph node matastasis (P<0.05), and no correlation with age, tumor size, histological grades, pTNM stages, histological types and menstruation status (P>0.05).There was no correlation between the expression of Topo-Ⅱαand any of the clinicopathological characteristics mentioned as above, such as age,tumor size, histological grades, et al (P>0.05).3 The relationship between expression of HIF-1αand P-gp: The positive expression rate of P-gp was 55.56%(20/36) in the group of HIF-1αpositive. The negative expression rate of P-gp was 82.61%(19/23) in the group of HIF-1αnegative. Expression of P-gp was positively correlated with HIF-1α(r=0.38, P<0.05). 4 The relationship between expression of HIF-1αand Topo-Ⅱα: There was no correlation between the expression of Topo-Ⅱαand HIF-1α(r=0.16, P >0.05).Conclusions: 1 The expression of HIF-1αis positively related to tumor size, histological gradesand and lymph node matastasis, its over expression shows that the invasion of breast cancer is even higher.2 The expression of P-gp has significantly positive correlation with lymph node matastasis, it may be a high risk factor for recurrence and matastasis of breast cancer.3 Topo-Ⅱαis over expressed in breast cancer tissues, and is negative in normal tissues, it may be a particular factor of drug resistance.4 The expression of HIF-1αis positively correlated with P-gp, and HIF-1αmay play an important role in multidrug resistance, which may provide a novel application strategy gene targeted therapy of breast cancer.5 There is no correlation between the expression of HIF-1αand Topo-Ⅱαin breast cancer.