Secreted ERBB3 Isoforms Are Serum Markers for Early Hepatoma in Patients with Chronic Hepatitis and Cirrhosis

Hsieh, Sen‐Yung; He, Jung-Ru; Yu, Ming-Chin; Lee, Wei‐Chen; Chen, Tse-Chin; Lo, Shao-Jung; Bera, Rabindranath; Sung, Chang-Mung; Chiu, Cheng‐Tang

doi:10.1021/pr200519q

Cited by 35 publications

(26 citation statements)

References 39 publications

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“…35 In addition, circulating HER3 has been demonstrated and found to be a serum marker for early hepatoma in patients with chronic hepatitis and cirrhosis. 36,37 Thus, our observations of elevated serum levels of HER3 in the patients with HER2-positive primary tumors agree with these earlier studies and support the theory of up-regulated expression of other EGF receptor family members as a potential mechanisms of resistance to trastuzumab. 8 There was good agreement between the new HER2 IFMA assay and the established CLIA HER-2/neu assay from Siemens.…”

Section: Discussionsupporting

confidence: 91%

Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4)

et al. 2017

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The use of trastuzumab in patients with breast cancer that overexpresses human epidermal growth factor receptor 2 has significantly improved treatment outcomes. However, a substantial proportion of this patient group still experiences progression of the disease after receiving the drug. Evaluation of the changes in expression of the human epidermal growth factor receptors could be of interest. Monoclonal antibodies against the extracellular domain of the human growth factor receptors, 2, 3, and 4, have been raised, and specific and sensitive immunoassays have been established. Sera from healthy individuals (Nordic Reference Interval Project and Database) were analyzed in the human epidermal growth factor receptor 2 assay (N = 805) and the human epidermal growth factor receptor 3 and 4 assays (N = 114), and reference limits were calculated. In addition, sera from 208 individual patients with breast cancer were tested in all three assays. Finally, the human epidermal growth factor receptor 2 assay was compared with a chemiluminescent immunoassay for serum human epidermal growth factor receptor 2/neu. Reference values were as follows: human epidermal growth factor receptor 2, <2.5 µg/L; human epidermal growth factor receptor 3, <2.8 µg/L; and human epidermal growth factor receptor 4, <1.8 µg/L. There were significant differences in human epidermal growth factor receptor 2 and human epidermal growth factor receptor 3 serum levels between the patients with tissue human epidermal growth factor receptor 2-positive and tissue human epidermal growth factor receptor 2-negative (p = 0.0026, p = 0.000011) tumors, but not in the serum levels of human epidermal growth factor receptor 4 (p = 0.054). There was good agreement between the in-house human epidermal growth factor receptor 2 assay and the chemiluminescent immunoassay. Our new specific antibodies for all the three human epidermal growth factor receptors may prove valuable in the development of novel anti-human epidermal growth factor receptor targeted therapies with sensitive immunoassays for measuring serum levels of the respective targets and in monitoring established treatment.

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Section: Discussionsupporting

confidence: 91%

Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4)

et al. 2017

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“…Alternative transcripts for ERBB3 resulting in naturally occurring soluble truncated isoforms including a 1.4 kb transcript of ERBB3 in gastric cancer cell lines [64] and an additional four novel transcripts (1.6, 1.7, 2.1, and 2.3kb) from ovarian cancer cell lines [65] encouraged researchers to identify these secreted isoforms of ERBB3 in Prostate [92–95], liver [96], breast [97, 98] and squamous cell carcinoma [99]. ERBB3 isoforms have also been expressed intracellularly in breast cancer cell lines [97] as well as in the nucleus of Schwann cells [100, 101], prostate [102–104] and breast [105, 106].…”

Section: Discussionmentioning

confidence: 99%

“…ERBB3 isoforms have also been expressed intracellularly in breast cancer cell lines [97] as well as in the nucleus of Schwann cells [100, 101], prostate [102–104] and breast [105, 106]. Secreted ERBB3 isoform p85 has been shown to inhibit the action of its ligand Neuregulin [98, 107], nuclear translocations act as co-transcriptional activators [108], possible post-translation modification and the tumour microenvironment are instructive to serum ERBB3 secretion from the cell [96] and functions yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Secreted isoforms such as ERBB3-S (1.4kb, 140aa homologous to the N terminus and a 43aa unique carboxy terminal sequence) equates to approximately half of domain I, p50 (1.6kb, 351aa homologous to the N terminus and a 30aa unique carboxy terminal sequence) equates to domain I, II and some of domain III, p45 (1.7kb, 310aa homologous to the N terminus and a 2aa unique carboxy terminal sequence) equates to domain I, II and some of domain III, p85 (2.1kb, 519aa homologous to the N terminus and a 24aa unique carboxy terminal sequence) equates to domain I, II,III and some of domain IV, p75 (2.3kb, 474aa homologous to the N terminus and a 41aa unique carboxy terminal sequence) equates to domain I, II and III [64, 65, 109] ERBB3 isoforms have been detected by a number of methods such as immunoprecipitation [65, 97, 107], immunohistochemistry [92] and ELISA [94–96]. Isoforms that have been detected using ELISA assays include p45 sERBB3 utilising a capture antibody of sequence aa20-643 (detection antibody sequence was not recorded) [94, 95] and 40-50kDa secreted isoforms (possible p45/p50) utilising both capture and detection antibodies with a sequence aa20-643 [96]. The Raybio ELISA kit utilised in our research uses a capture and detection antibody of sequence aa20-643 (personal communication Raybio) which accounts for most of the extracellular domain of ERBB3 and therefore would be able to capture and detect both truncated isoforms as well as the transmembrane ERBB3.…”

Section: Discussionmentioning

confidence: 99%

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ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1)

et al. 2017

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Devil Facial Tumour 1 (DFT1) is one of two transmissible neoplasms of Tasmanian devils (Sarcophilus harrisii) predominantly affecting their facial regions. DFT1’s cellular origin is that of Schwann cell lineage where lesions are evident macroscopically late in the disease. Conversely, the pre-clinical timeframe from cellular transmission to appearance of DFT1 remains uncertain demonstrating the importance of an effective pre-clinical biomarker. We show that ERBB3, a marker expressed normally by the developing neural crest and Schwann cells, is immunohistohemically expressed by DFT1, therefore the potential of ERBB3 as a biomarker was explored. Under the hypothesis that serum ERBB3 levels may increase as DFT1 invades local and distant tissues our pilot study determined serum ERBB3 levels in normal Tasmanian devils and Tasmanian devils with DFT1. Compared to the baseline serum ERBB3 levels in unaffected Tasmanian devils, Tasmanian devils with DFT1 showed significant elevation of serum ERBB3 levels. Interestingly Tasmanian devils with cutaneous lymphoma (CL) also showed elevation of serum ERBB3 levels when compared to the baseline serum levels of Tasmanian devils without DFT1. Thus, elevated serum ERBB3 levels in otherwise healthy looking devils could predict possible DFT1 or CL in captive or wild devil populations and would have implications on the management, welfare and survival of Tasmanian devils. ERBB3 is also a therapeutic target and therefore the potential exists to consider modes of administration that may eradicate DFT1 from the wild.

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“…(19) Therefore, specific anti-ErbB3 monoclonal antibodies could be useful in the diagnosis of these diseases.…”

Section: And Yangmentioning

confidence: 99%

Therapeutic Use of an Anti-ErbB3 Monoclonal Antibody

Yang²

2012

Hybridoma

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Emerging evidence suggests that the catalytically inactive ErbB3 (HER3) protein plays a fundamental role in normal tyrosine kinase receptor signaling as well as in aberrant functioning of these signaling pathways, resulting in several forms of human cancers and some mental disorders. Here we report the generation of a specific anti-ErbB3 antibody intended for use in diagnosing disease or therapeutic application. By using the hybridoma technique, one cell line (2E(12)C(3)) stably producing anti-ErbB3 antibody was obtained. Its molecular weight was about 185 kDa and its isotype was IgG 2a and κ, respectively. The affinity constant (Kaff) of the anti-ErbB3 MAb was 5.83×10(10) M(-1). This antibody may become a useful tool for diagnostic and therapeutic targeting of ErbB3-expressing cancers or helpful in highlighting the etiology of schizophrenia.

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Secreted ERBB3 Isoforms Are Serum Markers for Early Hepatoma in Patients with Chronic Hepatitis and Cirrhosis

Cited by 35 publications

References 39 publications

Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4)

Specific antibodies and sensitive immunoassays for the human epidermal growth factor receptors (HER2, HER3, and HER4)

ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1)

Therapeutic Use of an Anti-ErbB3 Monoclonal Antibody

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