Prognostic significance of ERRB3 overexpression in oral squamous cell carcinoma

doi:10.1016/0304-3835(95)03866-U

Cancer Letters

Volume 95, Issues 1–2, 16 August 1995, Pages 79-83

https://doi.org/10.1016/0304-3835(95)03866-U Get rights and content

Abstract

Immunohistochemical analysis of erbB3, as the third member of epidermal growth factor receptor gene family, was performed on 41 cases of oral squamous cell carcinoma, correlating the staining pattern with clinical outcome. High expression of erbB3 protein (ERBB3) was significantly associated with lymph node metastasis (P < 0.05), survival rate (P < 0.05) and mode of invasion (P < 0.01) in this series. These results demonstrated that ERBB3 expression may be helpful in identifying those oral squamous cell carcinomas with higher malignant potential.

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Cited by (54)

ErbB receptors in the biology and pathology of the aerodigestive tract
2009, Experimental Cell Research
The most common sites of malignancies in the aerodigestive tract include the lung, head and neck and the esophagus. Esophageal adenocarcinomas (EA), esophageal squamous cell carcinomas (ESCC), and squamous cell carcinomas of the head and neck (SCCHN) are the primary focus of this review. Traditional treatment for aerodigestive tract cancers includes primary chemoradiotherapy (CRT) or surgical resection followed by radiation (or CRT). Recent developments in treatment have focused increasingly on molecular targeting strategies including cetuximab (a monoclonal antibody against epidermal growth factor receptor (EGFR)). Cetuximab was FDA approved in 2006 for treatment of SCCHN, underscoring the importance of understanding the biology of these malignancies. EGFR is a member of the ErbB family of growth factor receptor tyrosine kinases. The major pathways activated by ErbB receptors include Ras/Raf/MAPK; PI3K/AKT; PLCγ and STATs, all of which lead to the transcription of target genes that may contribute to aerodigestive tumor progression. This review explores the expression of ErbB receptors in EA, ESCC and SCCHN and the signaling pathways of EGFR in SCCHN.
The hamster model of sequential oral oncogenesis
2008, Oral Oncology
Citation Excerpt :
Increased levels of the erbB2 protein have been reported in human OSCC, resulting mainly from amplification of its gene.75,76,78–83 On the other hand, several studies of human OSCC have reported overexpressed erbB3 mRNA and protein but no gene amplification.84–89 Concerning FGFR-2 and/or FGFR-3 immunoexpression in oral cancer, a study suggested increased intensity of both receptors in dysplasias and squamous cell carcinomas.90
Oral squamous cell carcinoma (OSCC) is a common cancer characterised by low survival rate and poor prognosis. The multistep process of oral carcinogenesis is affected by multiple genetic events such as alterations of oncogenes and tumour suppressor genes. The use of appropriate experimental animal models that accurately represent the cellular and molecular changes which are associated with the initiation and progression of human oral cancer is of crucial importance. The Syrian golden hamster cheek pouch oral carcinogenesis model is the best known animal system that closely correlates events involved in the development of premalignant and malignant human oral cancers. Therefore, we established an experimental system of chemically induced oral carcinogenesis in hamsters, in order to study different stages of tumour formation: normal mucosa, hyperkeratosis, hyperplasia, dysplasia, early invasion, well differentiated OSCC and moderately differentiated OSCC. We investigated the expression of oncogenes EGFR, erbB2, erbB3, FGFR-2, FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, apoptosis markers Bax and Bcl-2, tumour suppressor genes p53 and p16, and cell proliferation marker Ki-67 in the sequential stages of hamster oral oncogenesis. Here, we describe the findings of the experimental model in regard to the involvement of signal transduction pathways in every stage of cancer development. Increased apoptosis and cell proliferation were observed in early stages of oral oncogenesis. Furthermore, the increased expression of transmembrane receptors (EGFR, erbB2, FGFR-2 and FGFR-3) as well as the increased expression of nuclear transcriptional factors in early stages of oral cancer indicates that these molecules may be used as early prognostic factors for the progression of OSCC. Since the expression of both H-ras and N-ras do not seem to affect signal transduction during oral oncogenesis, it can be assumed that a different signalling pathway, such as the PI3K and/or PLCγ pathway, may be implicated in the pathogenesis of OSCC.
ERBB receptors in developing, dysplastic and malignant oral epithelia
2008, Oral Oncology
Citation Excerpt :
Overexpression of ERBB3 and ERBB4 mRNA has been detected in newly derived OSCC cell lines but has been reported as absent in long-term cultures.21 No information on ERBB3 and ERBB4 gene expression in OSCCs in vivo is available but an increase in the protein levels of these genes has been reported in 9–26% and 9–21% of OSCCs, respectively.18,19,22,23 More recently, primary OSCCs and their metastases have been reported to exhibit similar patterns of EGFR and ERBB2 expression, whereas ERBB3 and ERBB4 expression varied and was very low in both the primary carcinoma and the corresponding metastasis.24
Some oral squamous cell carcinomas (OSCCs) overexpress epidermal growth factor receptor (EGFR) but little is known about the receptor system overall during oral carcinogenesis. We studied all four ERBB receptors (EGFR, ERBB2-4) in developing (n = 2), normal (n = 7), dysplastic (n = 23) and malignant (n = 26) oral epithelia by means of immunohistochemistry. The investigations were supplemented by conducting reverse transcription-polymerase chain reactions in relation to 13 OSCC samples. All four ERBB receptors were detected in developing oral epithelium and, to a lesser degree, in mature oral epithelium. An increase in EGFR immunoreactivity was seen in 61% and 54% of dysplasias and OSCCs, respectively. The corresponding percentages for ERBB2 were 48 and 12, for ERBB3 48 and 43. ERBB4 nuclear staining was increased in 30% of dysplasias and 26% of OSCCs. Changes in ERBB receptor mRNA levels were not statistically significant. The results show that ERBB receptor profiles are specific to each tumour. Increased nuclear translocation of ERBB4 in some OSCCs may alter transcription of target genes and be associated with cancer progression. This information may be useful for clinicians as EGFR inhibitors are becoming treatment options in modern oncology.
Contribution of Membrane Mucins to Tumor Progression Through Modulation of Cellular Growth Signaling Pathways
2007, Current Topics in Developmental Biology
Citation Excerpt :
ErbB3, the favored dimeric partner of ErbB2, is overexpressed in several types of human tumors. These include clear cell carcinoma of soft tissue where it may serve as a diagnostic marker (Schaefer et al., 2004), oral squamous cell carcinoma where it correlates with lymph node metastases (Shintani et al., 1995), and breast tumors where it is commonly found cooverexpressed with ErbB2 (Naidu et al., 1998) and correlates with shorter relapse‐free survival (Bieche et al., 2003). ErbB3 is the catalytically deficient member of the ErbB family (Guy et al., 1994) and therefore must heterodimerize with other ErbB receptors in order to signal (Carraway and Cantley, 1994).
Mucins are large, heavily O‐glycosylated proteins expressed by epithelial tissues. The canonical function of membrane mucins is to provide protection to vulnerable epithelia by forming a steric barrier against assault, and by contributing to the formation of protective extracellular mucin gels. The aberrant overexpression of mucins is thought to contribute to tumor progression by allowing tumor cells to evade immune recognition, and by aiding in the breakdown of cell–cell and cell–matrix contacts to facilitate migration and metastasis. Recent evidence suggests that we should now modify our thinking about mucin function by considering their roles in signaling pathways leading to cellular growth control. Here we review the markedly divergent mechanisms by which membrane mucins, specifically MUC1 and MUC4, influence pathways contributing to cellular proliferation and survival. The cytoplasmic domain of MUC1 serves as a scaffold for the assembly of a variety of signaling proteins, while MUC4 influences the trafficking and localization of growth factor receptors, and hence their responses to external stimuli. We also discuss how tumor cells exploit these mechanisms to promote their own growth and metastasis.
HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer
2023, Cells
Nuclear HER3 expression improves the prognostic stratification of patients with HER1 positive advanced laryngeal squamous cell carcinoma
2021, Journal of Translational Medicine

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Cancer Letters

Abstract

References (20)

c-erbB-3 and C-erbB-2 protein expression in node-negative breast carcinoma — an immunocytochemical study

Eur. J. Cancer

Expression of epidermal growth factor receptor on oral squamous cell carcinoma

Br. J. Oral Maxillofac. Surg.

Differential expression of epidermal growth factor related proteins in human colorectal tumors

Overexpression of c-erbB-3 mRNA and its gene products in human SCC

Seikagaku

Prevalens of aberrant expression of the epidermal growth factor receptor in human cancers

Br. Med. Bull.

Antibodies to the autophospherylation sites of the epidermal growth factor receptor protein-tyrosine kinase as probes of structure and function

EMBO J.

erbB3; a third member of the erbB/epidermal growth factor receptor gene family: its expression in head and neck cell lines

Oto.-Rhino.-Laryngol.

Histologic classification and grading of malignancy in carcinoma of the larynx

Acta Radiol.

Cited by (54)

ErbB receptors in the biology and pathology of the aerodigestive tract

The hamster model of sequential oral oncogenesis

ERBB receptors in developing, dysplastic and malignant oral epithelia

Contribution of Membrane Mucins to Tumor Progression Through Modulation of Cellular Growth Signaling Pathways

HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer

Nuclear HER3 expression improves the prognostic stratification of patients with HER1 positive advanced laryngeal squamous cell carcinoma