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

Abstract

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.

Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth

“…Rare NRG1 gene fusions have, however, been identified as potential oncogenic drivers in CRC ( Jonna et al, 2019 ). In mouse models of intestinal tumorigenesis, deletion of Erbb2 and Erbb3 has been reported to both increase and decrease the tumor burden, depending on the genetic background ( Rojas et al, 2021 ). Our data from two independent sources showed that high stromal NRG1 expression correlates with improved survival in CRC, suggesting that in most CRCs, high stromal NRG1 expression is in fact beneficial.…”

Adding robustness to rigor and reproducibility for the three Rs of improving translational medical research

“…However, clinical trials with inhibitors blocking ERBB3 had little to no efficacy in the colon and showed a tendency toward promoting tumor progression (24). A subsequent preclinical robustness assay using different genetic backgrounds showed that deletion of Erbb3 results in a significant reduction in polyp number when performed on a 129S1/SvImJ background, but increased polyp number in B6J mice (25). These studies suggested that the outcomes of ERBB3 clinical trials would have been predicted using a robustness assay, which could have led to a more informed clinical trial.…”