ErbB4 Overexpression as an Antagonist of ErbB2/HER2/Neu Induced Human Breast Cancer Cell Proliferation
Annual summary 1 Aug 2003-31 Jul 2006
TULANE UNIV NEW ORLEANS LA
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To test the hypothesis that ERBB4 signaling suppresses ERBB2-mediated cell proliferation in breast cancer, we introduced ERBB4 into SKBR-3 and MCF-7 breast cancer cell lines, which overexpress and express normal levels of ErbB2, respectively. We found that ERBB4 induces apoptosis in over 40 of both SKBR-3 and MCF-7 cells. Significantly, the normal human mammary epithelial cell line hTERT-HME was resistant to ERBB4 induced apoptosis. Although ERBB4 apoptotic function requires kinase activity, neither MAPK nor Pl3-K signaling is involved in ERBB4 induced apoptosis. Further studies indicate that ERBB4 couples to the intrinsic apoptotic pathway through the mitochondrial proapoptotic protein Bak. A search for proapoptotic domains in ERBB4 revealed a putative BH3 domain within ERBB4 intracellular domain 410D. We found that 4lCD exhibits equivalent level of apoptotic activity as holoreceptor of ERBB4 and, in contrast, does not require the kinase activity. These findings suggest that ERBB4 kinase activity contributes to apoptosis by generating 4lCD from the cell membrane upon proteolytic cleavage. Mutation of the BH3 domain of 4lCD significantly decreases 4lCD-induced apoptosis. Taken together, our data indicate that ERBB4 functions as a proapoptotic BH3-only protein. The specificity of ERBB4 cell- killing for malignant cells further supports a tumor suppressor function for ERBB4.
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