Mucin Glycoproteins in Disease

Our laboratory is interested in the role of mucin glycoproteins in disease. Mucins are large molecular weight (250,000 to > 1 million Daltons) glycoproteins with from 50% to 90% of their molecular mass due to O-linked carbohydrates. Mucins have been incriminated in several diseases, in particular, carcinomas of the mammary gland, lung, colon, pancreas, stomach, prostate, ovary, and endometrium, in which a cell-associated mucin, MUC1, has been shown to be up-regulated and aberrantly expressed. Our primary research goals are: 1) to determine the function of the MUC1 cell-associated mucin molecule in cell adhesion, tumor progression, metastasis, and modulation of the immune system; and 2) to characterize MUC1 immunogens as a tumor vaccines.

Our hypothesis is that over-expression of the MUC1 protein by the cancer cells may confer an advantage upon the cell, perhaps by reducing the adhesive properties of cells and/or by modulating the immunogenicity of the tumor cells. The function of MUC1 may be dependent on its long, rod-like extracellular domain that may affect cell-cell and cell-matrix interactions. However, there is increasing evidence that MUC1 is involved in signal transduction. The cytoplasmic domain is phosphorylated (tyrosines and serines) and binds to proteins capable of transducing signals and/or interacting with the cytoskeleton. We have identified a number of interacting proteins and are presently characterizing the interactions biochemically. To address the function of MUC1 in tumor progression and metastasis, a mouse deficient in MUC1 (designated Muc1 in the mouse) has been created using homologous recombination. Mammary gland tumors were generated in the Muc1-deficient and control animals, using transgenic oncogene-expressing mice. Mammary gland tumors lacking Muc1 protein grew more slowly and metastasized less frequently than tumors expressing Muc1. Over expression of MUC1 in mouse mammary gland elicited mammary tumors, suggesting that MUC1 acts as an oncogene. Mutant forms of MUC1 are also being expressed, which may reveal important domains of the glycoprotein that function in mammary gland development, tumor progression and metastasis.

The ubiquitous and aberrant expression of MUC1 on most solid tumors (adenocarcinomas) suggests that MUC1 may be a potential immunotherapeutic reagent. Studies have shown that MUC1 has the potential to elicit tumor-specific immunity, to protect from tumor occurrence or prevent tumor recurrence. However, expression of MUC1 is not sufficient to stimulate the immune system effectively. There is a need for studies to devise effective presentation of tumor antigens to stimulate immune cells to kill tumor cells. We have developed transgenic mice expressing human MUC1 as a self molecule to provide an appropriate preclinical model. These mice spontaneously develop tumors of either the mammary gland or the pancreas. We are testing powerful new immunization approaches (dendritic cell/tumor cell fusions) to immunize the animals to MUC1 and other tumor antigens. Our goal is the prevention and treatment of spontaneous tumors and metastases of mammary gland and pancreatic tumors. Clinical trials in breast cancer will begin shortly.