Exploration On The Characteristics Of Breast Cancer In Qinghai And On The Relationship Between HIF-2, CA9, CA12 And The Pathogenesis Of Breast Cancer Carcinoma

Objective: Breast cancer is the most frequently diagnosed cancer among females worldwide. Incidence rates of breast cancer have been increasing in China, and it has also became the leading cancer site in Chinese females. Hypoxia plays a crucial role in the process of malignant tumor progression which involves Hypoxia inducible factors family( HIFs)and Carbonic anhydrases family( CAs) regulation. HIFs can trigger the expression of several genes related to many aspects of tumor progress under hypoxia. CAs were also regarded as important enzymes that involve in the tumor microenvironment p H. In this study, we aimed at the disease characteristics and clinical pathological traits of female breast cancer who live in Qinghai-Tibetan plateau by epidemiology, clinical pathological traits analysis and molecular mechanisms. Meanwhile, we try to explore the functions of HIF-2α、CA9、CA12 in the process of invasion and metastasis of breast cancer.Methods:1. All malignant tumours data of Qinghai university affiliated hospital from 2001-2010 was registered and analyzed in order to master the epidemiological Statistics, especially the information of breast cancer.2. To compare and analyze retrospectively the clinical characteristics and pathological features among 259 breast cancer patients who were diagnosed from 2001 to 2012,related clinical data including Han,Tibetan and Hui ethnic groups were analyzed retrospectively.3. Clinical data were collected and summarized in 94 patients with breast cancer. The expression of HIF-2α, CA9 and CA12 were detected, using immunohistochemistry of specimens. The relation between expressions and clinical-pathology was analyzed. Under normoxia, hypoxia, and after being pretreated with the JNK inhibitor SP600125, HIF-2α, CA9 and CA12 expressions were detected, adhesion and invasion assays were performed in MCF-7 cells and HIF-2α sh RNA cells, respectively.Results:1. Gastric,lung,liver,colorectal,esophageal cancer ranked the 1st to 5th most frequently diagnosed cancers in males. But gastric, lung, breast, cervical, colorectal cancer are the first fives frequently diagnosed cancers in females. The New cases per 100,000 population in different altitudes is about 47.39, 31.21, 10.91, respectively. There is statistical difference between different altitude(P < 0.001). A small amount of patients of breast cancer is distributed in ethnic groups.2. The proportion of breast cancer before 35 in Hui, Tibetan is higher than that of Han ethnic group; the age ranging from 36 to 50 years are more relatively common in Han, Tibetan than in Hui ethnic group. Han ethnic group patients with breast cancer have fewer fertility.3. There are higher expressions of HIF-2α in tumor classification 2 and clinical stage 2(P < 0.05). High expression of CA12 was observed in clinical stage 2(P < 0.05). CA9 expression is significantly correlated with CA12 expression(r=0.376, P=0.0001). HIF-2α expression is not correlated with both CA9 expression(P=0.21) and CA12 expression(P=0.27). Breast cancer cells in vitro showed that HIF-2α, CA9 and CA12 had an increase expression under hypoxia(1% O2). CA9 and CA12 expression was observed in HIF-2α sh RNA cells. JNK inhibitor SP 600125 reduced the HIF-2α expression and inhibited the adhesion and invasion of breast cancer cell. Slight inhibition effect on CA9 and CA12 expression was found.Conclusions:1. Qinghai province has an increasing trend in cancer incidence rate, but has a different features compared with other parts in China. The site of malignant tumours among many ethnic groups is different, and more common one is the digestive tract cancer. With the increase of altitude, the sums of cancers decrease except for Salar ethnicity. A small amount of patients with breast cancer is distributed in the ethnic minority.2. Among the breast cancer patients with Han,Tibetan and Hui ethnicity, there is no signifcant difference about the clinical characteristics and pathological features and molecular classification. Low fertility has a more important hazardous effect on Han ethnicity.3. HIF-2α, CA9 and CA12 are important hypoxia responsive elements in breast cancer. HIF-2α was involved in metastasis and invasion of breast cancer cells under hypoxia, by the involvement of c-Jun NH2-terminal kinase(JNK) signal pathway. CA9 and CA12 may tend to be regulated by HIF-1α more often than by HIF-2α under hypoxia.