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Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium
Daekee Lee, … , Jonathan M. Kurie, David W. Threadgill
Daekee Lee, … , Jonathan M. Kurie, David W. Threadgill
Published August 17, 2009
Citation Information: J Clin Invest. 2009;119(9):2702-2713. https://doi.org/10.1172/JCI36435.
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Research Article Oncology

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

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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 ApcMin 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.

Authors

Daekee Lee, Ming Yu, Eunjung Lee, Hyunok Kim, Yanan Yang, Kyoungmi Kim, Christina Pannicia, Jonathan M. Kurie, David W. Threadgill

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Figure 3

Response of mice with intestine-specific Erbb3 deletion to DSS treatment.

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Response of mice with intestine-specific Erbb3 deletion to DSS treatment...
(A) Body weights over time expressed as a percentage of the weight on the day of first exposure to DSS. Data are presented as mean ± SD. (B) Scoring of histological damage as described in Methods. Each dot represents an individual Erbb3 wild-type (filled circles), Erbb3 heterozygous (gray circles) or Erbb3 mutant (open circles) mouse. Histological scores were significantly different between Erbb3 mutant and either wild-type or heterozygous mice. Horizontal bars represent means. (C) Histological response of colons from Erbb3 mutant mice to DSS exposure. Top: Low-magnification view (original magnification, ×40) of colon cross section. Bottom: High-magnification view (×200) of inflammation *P < 0.05, unpaired Student’s t test.

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