Our goal is to understand the function of the tumor-associated mucin MUC1 in the progression of neoplasia in the mammary gland. The MUC1 protein (also called PEM, polymorphic epithelial mucin) is a heavily glycosylated transmembrane mucin glycoprotein that is highly expressed and aberrantly glycosylated by the majority of carcinomas and in particular, by >92% of primary and metastatic breast cancers. The MUC1 protein is a large, rod- like molecule, extending more than 250 nm beyond the cell surface, and it is often sialylated. The structural and biochemical characteristics may enable this protein to act by masking cell surface proteins, possibly those involved in adhesion or immune recognition. Our hypothesis is that expression of this protein benefits tumor cells and their metastatic counterparts, perhaps by reducing the adhesive properties of cells or by providing a protective layer around cells which may shield them from immune surveillance. MUC1 protein is also present at the apical surfaces of normal simple epithelial cells and is developmentally regulated, appearing initially about the time of lumen formation during organogenesis (day 11 in the mouse). Our hypothesis is that MUC1 may be involved in epithelial morphogenesis, perhaps acting to mask adhesive molecules present on the cell surface and aiding in the formation of a lumen. Since mammary gland cancer in the mouse closely resembles human breast cancer, our proposed experiments will allow us to analyze the functional role of Muc-l (the human gene designation is MUC1; the mouse gene is Muc- l) in the progression of neoplasia and in development. The current proposal will directly test the hypotheses by addressing the following specific aims: (l) By using gene targeting in embryonic stem cells, we will make a mouse strain with a mutated Muc-l gene, thus generating animals lacking Muc-l protein for testing its function in tumor progression and development (2) We will determine the effect of Muc-l deficiency on epithelial organogenesis, since it is important to understand its function in normal tissues as well as in cancer. (3) We will mate the mutant mice with transgenic mice that develop mammary gland tumors or induce tumors in these mice with chemicals or radiation to determine the effect of Muc-l deficiency on tumor formation and progression (growth and differentiation). (4) We will generate tumors that metastasize, thus enabling an analysis of the effect of the Muc-l protein on the rate of metastasis, percentage of tumors that metastasize, and organ specificity of metastatic lesions. (5) We will examine the susceptibility of tumors developing in the Muc-l-deficient and control mice to lysis by immune effector cells (NK cells and cytotoxic T lymphocytes). Our findings should be relevant to understanding more about the progression of breast cancer with the hope, ultimately, of better modulating progression of the disease.
Showing the most recent 10 out of 31 publications
