Overexpression of the oncogene c-erbB-2 (HER2/neu) in ovarian cancer: a new prognostic factor

doi:10.1016/S0301-2115(96)02630-9

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 71, Issue 2, February 1997, Pages 173-179

https://doi.org/10.1016/S0301-2115(96)02630-9 Get rights and content

Abstract

Ovarian cancer is the leading cause of death in gynecological cancers. To date, there are no prognostic factors in ovarian cancer that adequately account for tumor biology and the course of the disease. In recent years, some reports have described the prognostic significance of the amplification and overexpression of the oncogene c-erbB-2 (HER2/neu) in various human cancers, including ovarian cancer. The c-erbB-2 proto-oncogene is located on the long arm of chromosome 17. It encodes a 185 kD transmembrane glycoprotein receptor (p185^HER2) that has sequence similarities with the epidermal growth factor receptor (EGF-R). In ovarian cancer, the percentage of c-erbB-2 positive cases varies from 9 to 32%. Correlation with tumor stage and the degree of histological differentiation was not observed. The overexpression of c-erbB-2 is a new and statistically independent prognostic factor. The overexpression of oncogene c-erbB-2 in ovarian cancer can be detected by immunohistochemistry staining for the protein p185 and characterizes a group with unfavorable tumor biology and a significantly worse prognosis. Elevated serum levels of the c-erbB-2 oncoprotein have been identified in patients with various cancers known to overexpress the c-erbB-2 oncogene. The detection of a p185 oncoprotein fragment in the sera of ovarian cancer patients was recently published by our group. Antiproliferative effects of monoclonal antibodies directed against p185 have been demonstrated in breast cancer patients. This may lead to a new approach in ovarian carcinoma therapy, too, over and above the diagnostic aspects.

References (36)

GD Malkasian et al.
Prognostic significance of histologic classification and grading of epithelial malignancies of the ovary
Am J Obstet Gynecol
(1984)
K Alitalo et al.
Oncogene amplification in tumor cell
Adv Cancer Res
(1986)
S Nicholson et al.
Expression of EGF receptors associated with lack of response to endocrine therapy in recurrent breast cancer
Lancet
(1989)
ME van der Burg et al.
The prognostic value of epidermal growth factor receptors, determined by both immunohistochemistry and ligand binding assays, in primary epithelial ovarian cancer: a pilot study
Eur J Cancer
(1993)
JA Foekens et al.
Prognostic value of pS2 protein and receptors for epidermal growth factor (EGF-R)
Insulin-like growth factor-1 (IGF-1-R) and somatostatin (SS-R) in patients with breast and ovarian cancer
J Steroid Biochem Molec Biol
(1990)
JR Zabrecky et al.
The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells. SK-BR-3
J Biol Chemistry
(1991)
MC Moroni et al.
EGFR anti-sense RNA blocks expression of epidermal-growth-factor receptor and suppresses the transforming phenotype of a human carcinoma cell line
J Biol Chem
(1992)
B Sorbe et al.
Importance of histologic grading in the prognosis of epithelial ovarian carcinoma
Obstet Gynecol
(1982)
NF Hacker et al.
Primary cytoreductive surgery for epithelial ovarian cancer
Obstet Gynecol
(1983)
KD Swenerton et al.
Ovarian carcinoma: a multivariate analysis of prognostic factors
Obstet Gynecol
(1985)

JM Bishop

The molecular genetics of cancer

Science

(1987)

P Münzel et al.

Genomic alterations of the c-myc proto-oncogene in relation to the overexpression of c-erbB-2 and ki-67 in human breast cancer and cervix carcinomas

J Cancer Res Clin Oncol

(1991)

DJ Slamon et al.

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

(1989)

L Coussens et al.

Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene

Science

(1985)

CI Bargmann et al.

The neu oncogene encodes an epidermal growth factor receptor-releated protein

Nature

(1986)

T Yamamoto et al.

Am erb-B-related gene c-erbB-2 encodes a possible receptor protein similar to the epidermanl growth factor receptor

Nature

(1986)

CR King et al.

Amplification of a novel v-erbB-related gene in a human mammary carcinoma

Science

(1985)

DJ Slamon et al.

Human breast cancer correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science

(1987)

Cited by (110)

Site-Specific Antibody Drug Conjugates Using Streamlined Expressed Protein Ligation
2018, Bioconjugate Chemistry
Antibody-Drug Conjugates (ADCs) have been shown to produce clinical benefit in cancer patient thanks to their ability to target highly cytotoxic small molecules to tumor cells. However, the development of these complex molecules faces significant challenges due to the need to combine a large biologic drug with a small molecule drug to generate the desired bioconjugate. We describe here the use of a protein ligation methodology, based on the native chemical ligation reaction to generate site-specific Antibody-Drug Conjugates, which does not require the incorporation of unnatural modifications into the antibody. Fully native antibodies, with only the desired cytotoxic molecules attached, can be generated, thus minimizing the risk that additional modifications required for the site-specific conjugation pose a risk to the antibody activity. We demonstrate that our approach can be used to generate site-specifically modified ADCs, with potent in vitro and in vivo antitumor activity in a breast cancer tumor model.
Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors
2016, Molecular Therapy - Oncolytics
Citation Excerpt :
Targeting of the tumor-associated antigen HER2 by monoclonal antibodies has been a showcase for the development of targeted cancer medicine, which has first been authorized for the treatment of metastatic breast cancer.2 HER2, a receptor tyrosine kinase, is amplified in 15–30% of all breast3,4 and 9–32% of ovarian cancer patients.5 This cellular surface glycoprotein is an active “driver” oncogene, which has no known ligand, and its expression is clinically associated with poor prognosis.
To target oncolytic measles viruses (MV) to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins). These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC) marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.
Canertinib induces ototoxicity in three preclinical models
2015, Hearing Research
Citation Excerpt :
The ERBB family of receptors includes ERBB1 (EGFR), ERBB2 (Her-2/neu), ERBB3 (Her-3), and ERBB4 (Her-4) (Janne et al., 2007). Aberrant signaling of ERBB family members (Hynes and Stern, 1994; Leung et al., 1997) plays an important role in many cancers including breast (Sainsbury et al., 1985), ovarian (Meden and Kuhn, 1997), prostate (Schwartz et al., 1999), gastric (Hirono et al., 1995), laryngeal (Almadori et al., 1999), and indicate a more aggressive cancer phenotype (Klijn et al., 1994; Zinner et al., 2007). ERBB1 is overexpressed in the majority of NSCLC and is found frequently in lung squamous cell carcinoma (57–100%) whereas ERBB2 is found in lung adenocarcinomas (33%).
Neuregulin-1 (NRG1) ligand and its epidermal growth factor receptor (EGFR)/ERBB family regulate normal cellular proliferation and differentiation in many tissues including the cochlea. Aberrant NRG1 and ERBB signaling cause significant hearing impairment in mice. Dysregulation of the same signaling pathway in humans is involved in certain types of cancers such as breast cancer or non-small cell lung cancer (NSCLC). A new irreversible pan-ERBB inhibitor, canertinib, has been tested in clinical trials for the treatment of refractory NSCLC. Its possible ototoxicity was unknown. In this study, a significant dose-dependent canertinib ototoxicity was observed in a zebrafish model. Canertinib ototoxicity was further confirmed in two mouse models with different genetic backgrounds. The data strongly suggested an evolutionally preserved ERBB molecular mechanism underlying canertinib ototoxicity. Thus, these results imply that clinical monitoring of hearing loss should be considered for clinical testing of canertinib or other pan-ERBB inhibitors.
The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway
2013, Journal of Ethnopharmacology
Citation Excerpt :
The two most important proteins for ovarian cancer seem to be HER-2/neu and cyclin D1. Both proteins have prognostic significance because they are frequently overexpressed and implicated in experimental models of ovarian cancer (Meden and Kuhn, 1997; Hashimoto et al., 2011). The interaction between HER-2/neu and cyclin D1 appears to have therapeutic potential because several naturally occurring phytochemicals or synthetic drugs can reduce cyclin D1 expression through the down-regulation of HER-2/neu signaling, and the anti-HER-2/neu monoclonal antibody trastuzumab (Herceptin®) reduces cyclin D1 protein levels in human ovarian cancer cells (Abuharbeid et al., 2004; Menendez et al., 2005; Gianolio et al., 2012).
Antrodia camphorata (AC) is well known in Taiwan as a traditional Chinese medicinal fungus. However, the anticancer activity of AC against human HER-2/neu-overexpressing ovarian cancers is poorly understood.
The aim of this study is to investigate whether a submerged fermentation culture of AC can inhibit human ovarian carcinoma cell (SKOV-3) proliferation by suppressing the HER-2/neu signaling pathway. Cell viability, colony formation, DCFH-DA fluorescence microscopy, western blotting, HER-2/neu immunofluorescence imaging, flow cytometry, and TUNEL assays were carried out to determine the anti-cancer effects of AC.
MTT and colony formation assays showed that AC induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector β-catenin. We also observed that AC caused G₂/M arrest mediated by down-regulation of cyclin D1, cyclin A, cyclin B1, and Cdk1 and increased p27 expression. Notably, AC induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-9/-3 activation, PARP degradation, and Bcl-2/Bax dysregulation. An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas the antioxidant N-acetylcysteine (NAC) prevented AC-induced cell death, HER-2/neu depletion, PI3K/Akt inactivation, and Bcl-2/Bax dysregulation, indicating that AC-induced cell death was mediated by ROS generation.
These results suggest that AC may exert anti-tumor activity against human ovarian carcinoma by suppressing HER-2/neu signaling pathways.
Compounds Consisting of Quinazoline, Ibuprofen, and Amino Acids with Cytotoxic and Anti-Inflammatory Effects
2024, ChemMedChem
Pyrazolo[3,4-d]pyrimidine scaffold: A review on synthetic approaches and EGFR and VEGFR inhibitory activities
2023, Archiv der Pharmazie

View all citing articles on Scopus

View full text

Overexpression of the oncogene c-erbB-2 (HER2/neu) in ovarian cancer: a new prognostic factor

Abstract

Am J Obstet Gynecol

Adv Cancer Res

Lancet

Eur J Cancer

J Steroid Biochem Molec Biol

J Biol Chemistry

J Biol Chem

Importance of histologic grading in the prognosis of epithelial ovarian carcinoma

Obstet Gynecol

Primary cytoreductive surgery for epithelial ovarian cancer

Obstet Gynecol

Ovarian carcinoma: a multivariate analysis of prognostic factors

Obstet Gynecol

The molecular genetics of cancer

Science

Genomic alterations of the c-myc proto-oncogene in relation to the overexpression of c-erbB-2 and ki-67 in human breast cancer and cervix carcinomas

J Cancer Res Clin Oncol

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene

Science

The neu oncogene encodes an epidermal growth factor receptor-releated protein

Nature

Am erb-B-related gene c-erbB-2 encodes a possible receptor protein similar to the epidermanl growth factor receptor

Nature

Amplification of a novel v-erbB-related gene in a human mammary carcinoma

Science

Human breast cancer correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science