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Otol Neurotol. 2008 Jan;29(1):50-7. doi: 10.1097/mao.0b013e31815d4429.

ErbB and Nrg: potential molecular targets for vestibular schwannoma pharmacotherapy.

Author information

  • 1Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of California, San Diego, USA. jkdoherty@ucsd.edu

Abstract

OBJECTIVE:

Identify molecular targets for development of tumor-specific pharmacotherapeutics aimed at treating vestibular schwannomas (VSs). Activated epidermal growth factor receptor B (ErbB) 2 and ErbB3 are abundantly expressed in VS. ErbB2 signaling is essential for Schwann cell differentiation, survival, and proliferation. VS arise after loss of functional merlin, a putative tumor suppressor. Merlin internalizes ErbB2 receptors in rodent Schwann cells. Unregulated ErbB signaling may contribute to VS tumorigenesis.

STUDY DESIGN:

Molecular analyses, retrospective clinical correlation.

SETTING:

Tertiary referral center.

PATIENTS:

Thirty-eight specimens from patients operated for sporadic (n=21) and neurofibromatosis (NF) 2-related (n=17) VS.

INTERVENTION(S):

VS analyses via real-time polymerase chain reaction, immunohistochemistry, and correlation with patient clinical data.

MAIN OUTCOME MEASURE(S):

ErbB signaling molecule expression, tumor size, age, and NF2 status.

RESULTS:

VS upregulated epidermal growth factor (EGF) receptor in 68% (62% sporadic and 75% NF2-associated VS) and ErbB2 in 84% (76% sporadic and 94% NF2-related VS). ErbB3 was upregulated in 34%, and ErbB4 is downregulated in NF2-related VS. Of EGF receptor (EGFR) ligands, EGF was upregulated in all NF2-related VS, but none of the sporadic VS (p<0.01), and transforming growth factor alpha and beta-cellulin showed upregulation in 67% of NF2-related VS but not sporadic VS (p=0.02 and p=0.01, respectively). Neuregulin (Nrg) was upregulated in 86% of sporadic VS versus 19% of NF2-related VS (p<0.01). EGFR expression levels correlated directly with VS tumor size and inversely with patient age, whereas Nrg expression correlated directly with age (p=0.0005). EGF expression predicts NF2 status, whereas Nrg predicts non-NF2 status (p<0.01).

CONCLUSION:

These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.

PMID:
18199957
DOI:
10.1097/mao.0b013e31815d4429
[PubMed - indexed for MEDLINE]
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