Neuregulin expression, function, and signaling in human ovarian cancer cells

Gilmour, L.M. and Macleod, K.G. and McCaig, A. and Sewell, J.M. and Gullick, W.J. and Smyth, J.F. and Langdon, S.P. (2002) Neuregulin expression, function, and signaling in human ovarian cancer cells. Clinical Cancer Research, 8 (12). 3933-3942 . ISSN 1078-0432 . (Access to this publication is restricted)

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Abstract

PURPOSE: To investigate the expression and function of neuregulin (NRG) isoforms in ovarian cancer cell lines and tumor samples. EXPERIMENTAL DESIGN: Expression of NRG-1alpha and NRG-1beta proteins were detected by immunohistochemistry and mRNA by RT-PCR. erbB receptor levels and downstream signaling proteins were measured by Western blot analysis. RESULTS: Expression of NRG-1alpha and NRG-1beta proteins were detected by immunohistochemistry in 46 of 53 (87%) and 41 of 53 (77%) ovarian carcinomas, respectively. Serous carcinomas express higher levels of NRG-1alpha than endometrioid carcinomas (P = 0.017). NRG mRNA was detected by RT-PCR in 20 of 24 (83%) of ovarian carcinomas and eight of nine (89%) ovarian cancer cell lines. NRG-1alpha stimulated the growth of 5 of 14 cell lines whereas NRG-1beta stimulated 7 of 14 cell lines. The magnitude of NRG growth response was significantly associated with erbB2 expression levels. NRG-1alpha and -1beta (1 nM) growth-stimulated cell lines PE01 and PE06 demonstrated increased tyrosine phosphorylation of erbB2 and elevated tyrosine phosphorylation of ERK1 and ERK2. In contrast, the SKOV-3 cell line, the growth of which was unaffected, did not show these downstream responses. An anti-erbB3 receptor antibody (clone H3.105.5) blocked NRG-1beta growth changes and signaling in these cell lines. Conversely, the anti-erbB4 antibody (clone H4.72.8) enhanced NRG-beta1 growth stimulation. Herceptin also inhibited growth. CONCLUSIONS: With NRG expression in the majority of ovarian carcinomas and cell lines, there is the potential for autocrine regulation of cell growth. Interfering with ligand-receptor interactions by receptor blocking antibodies suggests erbB3 is primarily involved in NRG-1beta-induced proliferation, with erbB4 having a more complex role.

Item Type: Article
Uncontrolled keywords: Adenocarcinoma/metabolism/pathology Adenocarcinoma, Clear Cell/metabolism/pathology Blotting, Western Carcinoma, Endometrioid/metabolism/pathology Cystadenocarcinoma, Serous/metabolism/pathology DNA Primers/chemistry Female Humans Immunoenzyme Techniques Neuregulin-1/genetics/*metabolism Ovarian Neoplasms/*metabolism/pathology Phosphorylation Protein Isoforms RNA, Messenger/metabolism Receptor, Epidermal Growth Factor/genetics/metabolism Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured
Subjects: Q Science
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculties > Science Technology and Medical Studies > School of Biosciences > Biomedical Research Group
Depositing User: Bill Gullick
Date Deposited: 04 Sep 2008 14:14
Last Modified: 05 Sep 2011 23:34
Resource URI: http://kar.kent.ac.uk/id/eprint/3987 (The current URI for this page, for reference purposes)
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