Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor

Overexpression of the membrane mucin MUC4/Sialo-mucin complex (SMC) has bee n observed during malignant progression of mammary tumors in both humans an d rats, suggesting that deregulation of MUC4/SMC expression might facilitat e development of these malignancies, As previously reported, overexpression of SMC results in suppression of both cell adhesion and immune killing of tumor cells, SMC also acts as a ligand for ErbB2/Neu, modulating phosphoryl ation of the receptor tyrosine kinase in the presence and absence of heregu lin. The present studies investigated the effect of Muc4/SMC up-regulation on primary tumor growth using a tetracycline-inducible SMC expression syste m in a xenotransplanted tumor model. SMC upregulation provoked rapid growth of transfected A375 melanoma in nude mice. Up-regulation of SMC, however, did not significantly increase proliferation of A375 cells in vitro, Instea d, a strong suppression of apoptosis was observed in situ in SMC-overexpres sing tumors, These data suggest that Muc4/SMC expression promotes tumor gro wth in vivo at least in part via suppression of tumor cell apoptosis, Impor tantly, reduction of apoptosis was also observed in vitro, indicating that anti-apoptotic effect of SMC is independent of tumor-host interactions, The se findings strongly suggest that SMC up-regulation alters intracellular si gnaling to favor cell survival, providing for the first time evidence for t he regulation of programmed cell death by a gene of the MUC family.