The Preliminary Study Of The Function And Mechanism Of MUC1 In Breast Carcinogenesis And Responsing To γ-irradiation By Mice Model

Part I: The Preliminary Study of the Function and Mechanism of Muc1 in Breast TumorigenesisMUC1(Mucin1)is a 120-225 KDa transmembrane glycoprotein expressed on the luminal surface of secretory epithelia,such as mammary,ovary,respiratory tract,gastrointestinal tract and acts as a lubricant and protective effect on normal epithelial to protect cells form outer bacteria,viruses,and dust particles.MUC1 gene spans approximately 4kb,encoding a primarily single peptide which is then cleaved into N-terminal and C-terminal subunits respectively in the endoplasmic reticulum,and on the cell membrane the two subunits form a stable heterologous dimerization body.Clinical study found that among 70% of solid tumor cells(including thyroid cancer,lung cancer,colorectal cancer,etc)MUC1 exhibits a depolarized expression pattern,and expression level up to 50-100 times higher than in normal cells.This aberration is particularly found in more than 90% of breast tumor patients and associated with malignancy and poor prognosis.Our previous study found that mammary gland duct and acini in transgenic mice overexpressing MUC1-CD exhibited a hyperplasia phenotype.As we all know,tumorigenesis is a multi-step process involving in multi-factors.Overexpression of MUC1-CD in our mouse model showed only precancerous lesions such as mammary gland hyperplasia,suggesting that MUC1-CD might play an important role in initiating tumorigenesis.In order to stimulate the multi-factors of breast tumorigenesis,this study introduced Her2 gene in to our preivously established MUC1-CD overxpression mouse model.Through long term of mice reproduction and observation of breast tumor incidence,MUC1 apparently improved mouse mammary tumor incidence and shortend life span.Futhur analysis of molecolar mechanism as well as collaboration of MUC1 and HER2 in breast tumorigenesis reveals some novel regulated genes and signal pathways,providing theoretical evidence and experimental platform for furthur molecular subtyping of breast tumor.By means of gene chip,we have preliminarily found three pathways,namely,lysine degradation,aldosterone-regulated sodium reabsorption and focal adhesion,which may be the key to the crosstalk of MUC1 and HER2.Besides,There are almost half of genes MUC1 regulated apparently related to lipid metabolism,suggesting a novel and significant role of MUC1 in carcinogenesis.The research results may be of great importance to breast cancer-associated early diagnosis,therapy,and prognosis.Part II Study on The Function and Mechanism of MUC1 in Irradiation StressOur study has previously found that MUC1 promotes DNA damage repair via interacting with ATM,rendering MUC1 overexpression cells resistant to irradiation therapy.To furthur elucidate the function of Muc1 in DNA damage response in mice model,a Muc1 gene conditional knockout mouse model was constructed.By mating with EIIa-Cre transgenic mice,Muc1 systemic knock out mice model is established.Muc1 gene expression profilling reveals that Muc1 gene is highly expressed in lung,stomach,and relatively low expression in uterus,kidney,smal intestine,testis and breast.Preliminary phenotype analysis found that Muc1 gene knock out mice exhibited no apparent difference compared with widetype littermates.However,challenged with γ-irradiation at dose of 13 Gy,Muc1 knock out mice exhibted more severe damage than widetype littermates,suggesting that MUC1 meditates in protecting tissues from damage under irradiation,consistent with our previous foundings.This research proved for the first time in vivo that MUC1 plays a protective role in irradiation,and furthur confirmed the evolutionary discovery that MUC1 promotes DNA damage repair previously found in our group,providing new field in study of the biological function of MUC1.