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Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium

Title
Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium
Authors
Lee D.Yu M.Lee E.Kim H.Yang Y.Kim K.Pannicia C.Kurie J.M.Threadgill D.W.
Ewha Authors
이대기
SCOPUS Author ID
이대기scopus
Issue Date
2009
Journal Title
Journal of Clinical Investigation
ISSN
0021-9738JCR Link
Citation
vol. 119, no. 9, pp. 2702 - 2713
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the Apc Min mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/ AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.
DOI
10.1172/JCI36435
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자연과학대학 > 생명과학전공 > Journal papers
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