The Study Of Relationship Between HIF-1α, VEGF And TP Expression In Mammary Cancer And Angiogenesis

Objective: Mammary cancer accounts for 7% to 10% in all the maligant cancers in China.The survey of epidemiology shows that about 1.2 million women suffer mammary cancer all over the globe every year and about 500,000 women die of mammary cancer. At present, mammary cancer has become one of the most common and frequently-occurring maligant cancers for women throughout the world. The incidence of mammary cancer increases by 2% per year and causative agent is not clear so far. In World Mammary Cancer Conference held in Canada,2002, the world health organization pointed out that the incidence of mammary cancer nearly doubled over the past 20 years.So it is significant to prevent and control mammary cancer.Hypoxia is a basic characteristic of micro-environment of solid tumors. Angiogenesis and celluar adaptation to hypoxia represent a critical step in tumorigensis. The key factor regulating cellular O₂ homeostasis is hypoxia-inducible factor(HIF-1),which transcriptionally regulate expression of several dozens of the target genes. HIF-1 activates transcription of the genes that are involved in crucial aspects of cancer biology,including angiogenesis,cell survival,glucose metabolism,invasion and metastasis. HIF-1 is a heterologous transcription factor composed of HIF-1αand HIF-1β,of which the former is a subunit specifically regulated by oxygen.It decides HIF-1's active and is the only transcription factor which can play active in the state of hypoxia.It plays role by starting the transcription expression of target gene via the combination with the hypoxia target gene.Vascular endothelial growth factor(VEGF) is also named vascular permeation factor(VPF),it has many functions.it can stimulate the proliferation, immigration, enhancing the vasopermeability, promoting vasoformation through conjunction with its special receptor. It's the most critical angiogenesis promoting factor what have known. Many factors regulate its expression, hypoxia is the strongest factor that introduces the expression of VEGF, and VEGF is one of the regulation target gene of HIF-1α.Breast carcinoma is a kind of malignant tumor with dependent. At present the discovered 18 kinds of promoting vascularization factors affect the activity phenotype transform of neogenesis blood vessel. Tymidine phosphorlase (TP) is one of them. TP effects thymine deoxyriboside especially,let it make reverse phosphorylation.Its production 2-dDR can introduce the significant vascularization .The expression of TP in tumor tissue is affected by many factors. Furthermore, the TP expression of different cell has different clinical meaning.This project use immunohistochemistry (SP assay)to observe the expression of HIF-1α,VEGF,TP in breast carcinoma tissue and normal mammary gland tissue and the relation with vascularization.At the same time ,we detect the expression of CD34 and furtherly definite the promoting vascularization of HIF-1α,VEGF,TP. It will help decide prognosisand instruct treatment for overexpression of TP if we understand the expression and regulationg of HIF-1α,VEGF,TP and the relation of prognosis, treatment and the other clinical factors.Material and method :This project use immunohistochemistry (SP assay) to detect the expression of HIF-1α,VEGF and TP in breast cancer tissue 37 cases which were confirmed by pathology. Software SPSS10.0 was used to treat the experimental datax²-test and fisher precisely probability calculation were used to compare the rates .P values less than 0.05 were considered significant.Results: (1) Expression rate of HIF-12 in normal mammary glandular tissue and breast cancer tissue was 6.7% (1/15)and 78.4%(29/37).The positive expression rate of HIF-1αin breast cancer was different with that in normal tissue,the different was significant (x²=22.487,P<0.01). The expression in breast cancer tissue with district lymph node metabasis(19/20) was obviously higher than that without metabasis(10/17).The expression in III-stage breast cancer tissue was higher than II -stage breast cancer tissue(P<0.05) and obviously higher than I-stage breast cancer tissue. The MVD value of positive group is obviously higher than that of negative group and the difference are significant(P<0.01).(2) The positive expression rate of VEGF in breast cancer tissue is 70.3%(26/37), which is significantly higher than that in normal tissue(0/15,P<0.05). The positive expression rate of VEGF in breast cancer tissue with lymph node metastatic(17/20). The positive rate in stage II-III is obviously higher than that in stage I (P<0.01).The MVD value of VEGF positive group is higher than that of negative group and statistical significance was found between two different groups(P<0.05).(3) The positive expression rate of TP in breast cancer tissue(86.5%,32/37) is obviously higher than that in normal tissue(53.3%,8/15). The positive expression rate of TP in breast cancer with lymph node metastasis (95.0%,19/20) is higher than that without lymph node metastasis(76.5%,13/17). The positive rate in stage II-III is obviously higher than that in stage I(P<0.01). The MVD value of TP positive group is obviously higher than that of negative group and the difference is significant (P< 0.01).(4) Both of HIF-1αand VEGF are found highly expressing in breast cancer tissue ,they show direct correlation between them (r_s=0.357, P<0.05).Positive rate of TP is 25.12±3.25 in HIF-1α(+)group ,and obviously higher than 13.33±2.87 in HIF-1α(-)group (t= 9.778, P<0.01). TP expression density grows higher and higher with the expression rate of HIF-1αand VEGF grows.Conclusions: (1) The positive rate of the expression of HIF-1α, VEGF and TP in the tissues of breast carcinoma was significant higher than that in the tissues of normal breast. The expression of HIF-1α, VEGF and TP in breast carcinoma I stage and the over expression in breast carcinoma II stage and III stage indicated that cells hypoxia happened before canceration, and during the whole procedure of occurrence and development of carcinoma. The high expression of HIF-1α, VEGF and TP were related with development of breast. It indicated that the expression of VEGF, VEGF and TP was important for vascularization of breast carcinoma.(2) HIF-1αin the tissues of breast carcinoma was the positive correlation with VEGF expression and TP , which showed HIF-1αwas center affect during hypoxia. The multiplicity expression of VEGF and TP stimulated vascularization of carcinoma.(3)There was the positive correlation between the expression of HIF-1α, VEGF and TP and lymph node metastasis and TNM stage. They were related with the prognosis of breast carcinoma.