Sialomucin complex (SMC, rat Muc4) is a unique membrane mucin composed of a mucin subunit ASGP-1 and ASGP-1 and a trans-membrane subunit ASGP-2, derived from a single gene and originally isolated from a highly metastatic ascites rat mammary adenocarcinoma. Preliminary studies suggest that Muc4 over-expression correlates with tumor progression in human breast cancers. SMC is bifunctional as well as heterodimeric. The mucin has potent anti-recognition properties, blocking cell-cell and cell-matrix adhesions and protecting transfected tumor cells from immune cell lysis. ASGP-2 has two EGF-like domains and can act as a novel intramembrane ligand for the receptor tyrosine kinase ErbB2 to potentiate the phosphorylation of the heterodimeric receptor complex ErbB2/ErbB3. Our recent studies on the role of SMC in tumor progression have shown that it can act as an anti-apoptotic agent. Finally, ASGP-1 has the potential to act as a pro-adhesive component in tumor extravasation, as it can carry the ligand SLex for selectins implicated in metastasis. This proposal is directed primarily toward understanding the roles of SMC in tumor progression. Our recent studies indicate that SMC is tightly regulated in the mammary gland, specifically by TGF beta. Our working hypothesis for this proposal is that loss of SMC regulation leads to its over-expression and potentiates mammary tumor progression. We propose experiments to test the role of SMC in tumor progression and to examine the mechanism by which SMC expression is regulated by TGF beta.
Specific aim 1 will investigate the function(s) of SMCIMuc4 in ErbB2-induced mammary tumors in vivo using over-expression by transgenic technology.
Specific aim 2 will investigate the function(s) of SMCIMuc4 in normal mammary gland and its role in early tumor progression by blocking SMC expression by retroviral transfection of a ribozyme followed by mammary tissue transplantation.
Specific aim 3 will investigate a primary mechanism for regulating SMCIMuc4 expression in normal rat mammary gland, post-translational repression of SMC processing by TGFB. The hypothesis is that signaling through the SMAD pathway contributes to regulating a protease involved in post-translational processing of SMC precursor.
Specific aim 4 will investigate the role of SMC SLex in tumor metastasis. These studies are directed toward providing the evidence for SMC/MUC4 contributions to tumor progression as a prelude to developing methods for therapeutic targeting of this component.
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