Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR

ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-ApcMin/+ mice. Contrary to the previous...

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Bibliographic Details
Published in:PLoS genetics 2021-11, Vol.17 (11), p.e1009931-e1009931
Main Authors: Mantilla Rojas, Carolina, McGill, Michael P, Salvador, Anna C, Bautz, David, Threadgill, David W
Format: Article
Language:English
Subjects:
Adenomatous Polyposis Coli Protein - genetics
Animals
Azoxymethane
Biology and Life Sciences
Cancer
Cell proliferation
Cell Proliferation - genetics
Clinical trials
Colon
Colon - metabolism
Colon - pathology
Colonic Polyps - genetics
Colonic Polyps - pathology
Colonic Polyps - therapy
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Colorectal Neoplasms - therapy
Disease Models, Animal
Epidermal growth factor
Epidermal growth factor receptors
ErbB Receptors - genetics
ErbB-3 protein
Gene Expression Regulation, Neoplastic - genetics
Gene Silencing
Genetic aspects
Humans
Intestinal Mucosa - metabolism
Intestinal Mucosa - pathology
Intestinal polyps
Intestinal Polyps - genetics
Intestinal Polyps - pathology
Intestinal Polyps - therapy
Intestine
Kinases
Medicine and Health Sciences
Metastasis
Mice
Polyps
Receptor, ErbB-3 - antagonists & inhibitors
Receptor, ErbB-3 - genetics
Research and Analysis Methods
Small intestine
Therapeutic targets
Tumorigenesis
Tumors
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Summary:ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-ApcMin/+ mice. Contrary to the previous report showing a significant reduction in intestinal polyps with ablation of ERBB3 on a B6;129 mixed genetic background, we observed a significant increase in polyp number with ablation of ERBB3 on C57BL/6J compared to control littermates. We confirmed the genetic background dependency of ERBB3 by also analyzing polyp development on B6129 hybrid and B6;129 advanced intercross mixed genetic backgrounds, which showed that ERBB3 deficiency only reduced polyp number on the mixed background as previously reported. Increased polyp number with ablation of ERBB3 was also observed in C57BL/6J mice treated with azoxymethane showing the effect is model independent. Polyps forming in absence of ERBB3 were generally smaller than those forming in control mice, albeit the effect was greatest in genetic backgrounds with reduced polyp numbers. The mechanism for differential polyp number in the absence of ERBB3 was through altered proliferation. Backgrounds with increased polyp number with loss of ERBB3 showed an increase in cell proliferation even in non-tumor epithelia, while backgrounds showing reduced polyp number with loss of ERBB3 showed reduced cellular proliferation. Increase polyp number caused by loss of ERBB3 was mediated by increased epidermal growth factor receptor (EGFR) expression, which was confirmed by deletion of Egfr. Taken together, this study raises substantial implications on the use of ERBB3 inhibitors against colorectal cancer. The prediction is that some patients may have increased progression with ERBB3 inhibitor therapy, which is consistent with observations reported for ERBB3 inhibitor clinical trials.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1009931