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Granulosa Cell Tumors Express erbB4 and Are Sensitive to the Cytotoxic Action of Heregulin-ß2/PE40¹

Cancer Research Program [C. F., R. J. F., D. I. Q., R. J. B., R. J. D., R. L. S.] and Co-operative Research Centre for Biopharmaceutical Research [R. J. F., R. J. D., R. L. S.], Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia

The molecular genetic events involved in the etiology of human granulosa cell (GC) tumors, which represent 7% of all malignant ovarian neoplasms, are unknown. Amplification and/or overexpression of the ERBB genes are a feature of many cancer types, and overexpression of erbB2 correlates with poor prognosis in epithelial ovarian cancer. In the present study, we used immunohistochemistry to determine the level and frequency of expression of different erbB receptors in GC tumors. Ten of 12 tumors expressed erbB4 at moderate to high levels in >50% of cancer cells, whereas erbB2 (6 of 12) and erbB3 (2 of 12) were expressed less frequently. Western blot experiments showed that the only available GC tumor cell line, COV434, also expressed erbB receptors. Heregulin (HRG)-ß2, a ligand for erbB3 and erbB4 receptors, stimulated tyrosine phosphorylation of the erbB receptors, which was accompanied by activation of Erk1 and Erk2, two mitogen-activated protein kinases with a functional role in mitogenesis. Importantly, HRG increased cell proliferation in COV434 cells, and treatment with HRG/PE40, a ligand toxin shown previously to be cytotoxic against human breast cancer cells overexpressing erbB receptors, led to a dramatic and irreversible decrease in cell number. These results indicate that erbB receptor signaling pathways may be critical in the control of GC tumor cell proliferation and that HRG/PE40 is a potential therapeutic agent for the treatment of GC tumors.

¹ This work was supported by grants from Association pour la Recherche sur le Cancer (to C. F.), the National Health and Medical Research Council of Australia, the New South Wales State Cancer Council, the St. Vincent's Clinic Foundation, and the Australian Government's Co-operative Research Centre Program.

² To whom requests for reprints should be addressed, at Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia. Phone: 61-2-9295-8322; Fax: 61-2-9295-8321; E-mail: r.sutherland@garvan.unsw.edu.au.

Received 12/31/97. Accepted 3/19/98.

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