Dataset Information

Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3.

ABSTRACT: The enteric nervous system mediates reflexes independently of the brain and spinal cord and transmits signals bidirectionally between the gut and the brain. Hirschsprung disease and chronic intestinal pseudo-obstruction (CIPO) and pediatric CIPO are examples of congenital defects that impair gastrointestinal motility. In this issue of the JCI, Thuy-Linh Le et al. analyzed eight patients with defects in tissue that arose from the neural crest. The patients carried homozygous or heterozygous variants in ERBB3 or ERBB2, which encode transmembrane epidermal growth factor receptors that bind neuroregulin 1 (NRG1). Notably, the genetic variants resulted in loss of function with decreased expression or aberrant phosphorylation of the ERBB3/ERBB2 receptors. Experiments using mice revealed that Erbb3 and Erbb2 were expressed in enteric neuronal progenitor cells. This study is an outstanding example of descriptive observation that begs for mechanistic exploration to reveal precisely how the NRG1/ERBB3/ERBB2 pathway influences ENS development.

SUBMITTER: Gershon MD

PROVIDER: S-EPMC7954584 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3.

Gershon Michael D MD

The Journal of clinical investigation 20210301 6

The enteric nervous system mediates reflexes independently of the brain and spinal cord and transmits signals bidirectionally between the gut and the brain. Hirschsprung disease and chronic intestinal pseudo-obstruction (CIPO) and pediatric CIPO are examples of congenital defects that impair gastrointestinal motility. In this issue of the JCI, Thuy-Linh Le et al. analyzed eight patients with defects in tissue that arose from the neural crest. The patients carried homozygous or heterozygous varia ...[more]

PMID: 33720042

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Project description:Background:Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC. Methods:We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided. Results:ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival. Conclusions:MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3.

Project description:ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast cancer patients unveiled that higher ERBB3 mRNA expression correlates with shorter relapse-free survival in basal-like breast cancers, despite low ERBB3 expression in this breast cancer subtype. Administration of neuregulin 1 beta (NRG1β) significantly affected neither cellular proliferation nor the basal migratory ability of basal-like/triple-negative quasi-normal MCF10A breast cells, cultured in mono-layer conditions. Furthermore, no significant regulation in cell morphology or in the expression of basal/myoepithelial and luminal markers was observed upon stimulation with NRG1β. In non-adherent conditions, NRG1β administration to MCF10A cells did not significantly influence cell survival; however, it robustly induced cell growth as spheroids (3D growth). Intriguingly, a remarkable upregulation of ERBB3 and ERBB2 protein abundance was observed in 3D compared to 2D cell cultures, and NRG1β-induced 3D cell growth was efficiently prevented by the anti-HER2 monoclonal antibody pertuzumab. Similar results were obtained by the analysis of basal-like/triple-negative breast cancer cellular models, MDA-MB-468 and MDA-MB-231 cells, in which NRG1β induced anchorage-independent cell growth that in turn was prevented or reduced by the simultaneous administration of anti-HER2 neutralizing antibodies. Finally, the ability of pertuzumab in suppressing NRG1β-induced 3D growth was also evaluated and confirmed in MCF10A engineered with HER2-overexpression. We suggest that the NRG1/ERBB3/ERBB2 pathway promotes the anchorage-independent growth of basal-like breast cancer cells. Importantly, we provide evidence that ERBB2 neutralization, in particular by pertuzumab, robustly inhibits this process. Our results pave the way towards the development of novel anticancer strategies for basal-like breast cancer patients based on the interception of the NRG1/ERBB3/ERBB2 signaling axis.

Dataset Information

Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3.

Publications

Hirschsprung disease and more: dysregulation of ERBB2 and ERBB3.

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