MUC1 is often highly overexpressed in breast cancer relative to normal breast epithelial cells. Recently, Wei et al. dem onstrated that the C terminal fragment of MUC1 associates with the DNA binding domain of the estrogen receptor. Such binding stabilized the estrogen receptor by namely reducing ubiquiti nation and proteasomal degradation of the estrogen receptor. MUC1 also increased recruitment of coactivators SRC1 and GRIP1 and was associated with increased ER mediated transcription. Taken together, these data suggest a role for MUC1 oncoprotein in estrogen mediated cell growth and sur vival of breast cancer cells. Antibodies targeting MUC1 epitopes studied in human breast tumor biopsies bind to at least 90% of invasive breast neo plasms. The overexpression of MUC1 correlates with adhesion and invasion of breast cancer cells in vitro.

Breast cancer patients who demonstrate MUC1 overexpres sion in greater than 75% of tumor cells and aberrant subcellu lar localization have Inhibitors,Modulators,Libraries significantly poorer disease free and overall survival. AS1402 is a humanized IgG1 monoclonal antibody which binds the extracellular MUC1 peptide sequence, PDTR.These Inhibitors,Modulators,Libraries sequences are not exposed in normal cells because of full gly cosylation, but aberrant glycosylation in cancer cells exposes the epitope to the antibody. AS1402 is a potent inducer of antibody dependent cellular cytotoxicity, specifically against MUC1 expressing tumor cells. Snijdewint et al. demonstrated ADCC elicited by AS1402 in vitro in the breast tumor cell line ZR 75 1, in three bone marrow derived tumor cell lines from breast cancer patients, and in Chinese hamster ovary cells transfected with the Inhibitors,Modulators,Libraries human MUC1 gene, by using peripheral blood mononuclear cells from healthy donors.

Cell lines that did not express human MUC1 were not susceptible to ADCC in the presence of AS1402. Very weak or no killing of the MUC1 positive target cell line with human PBMCs was noted Inhibitors,Modulators,Libraries in the absence of AS1402. These authors also demonstrated a strong reduction in specific AS1402 dependent cell killing of ZR 75 1 cells when the PBMCs were depleted of CD56 cells cells. Par tial to Inhibitors,Modulators,Libraries complete depletion of either CD4, CD8, or CD19 cells from the PBMCs did not significantly reduce the ADCC. Moreover, the ADCC activity of AS1402 was shown to be dependent on the involve ment of the FcIII receptor on NK cells. Immunotherapy for the treatment of cancer is an attractive alternative to cytotoxic chemotherapy. Since the approval in 1997 of rituximab for the therapy of non despite Hodgkin lymphoma, several other antibodies have been licensed for dif ferent cancers.