title: The outcome of heregulin-induced activation of ovarian cancer cells depends on the relative levels of HER-2 and HER-3 expression.
abstract: Members of the epidermal growth factor receptor family of tyrosine kinases, including epidermal growth factor receptor, c-erbB-2 (HER-2), c-erbB-3 (HER-3), and c-erbB-4 (HER-4), can be coexpressed at different levels in nonhematopoietic tissues. Amplification and overexpression of HER-2 is found in approximately one-third of cancers that arise in the breast and ovary. In our previous studies, heregulin (HRG) and anti-HER-2 antibodies inhibited proliferation, increased invasiveness, and enhanced tyrosine autophosphorylation of SKBr3 breast cancer cells that overexpressed HER-2. In the present report, the effects of HRG and anti-HER-2 antibody have been compared in six ovarian cancer cell lines. HRG inhibited anchorage-independent growth of SKOv3 cells that overexpressed HER-2 (10(5) receptors/cell) but stimulated the growth of OVCA420, OVCA429, OVCA432, OVCA433, and OVCAR-3 cells that expressed lower levels of the receptor (10(4) receptors/cell). Thus, cell lines with a high level of HER-2 relative to HER-3 or HER-4 were growth inhibited, whereas cell lines with lower levels of HER-2 were growth stimulated by HRG. Stimulation or inhibition of clonogenic growth did not correlate with endogenous expression of HRG or with the impact of exogenous HRG on phosphorylation of HER-2, HER-3, or HER-4. Anti-HER-2 antibodies inhibited the growth of SKOv3 cells but failed to affect the growth of the other cell lines. In OVCAR-3 cells that had been transfected with HER-2 cDNA to increase expression to 10(5) receptors/cell, HRG inhibited rather than stimulated growth. Conversely, when HER-2 expression by SKOv3 cells was downregulated by transfection of the viral E1A gene, HRG stimulated rather than inhibited growth. To evaluate the relative importance of HER-3 and HER-4, NIH 3T3 cells were cotransfected with HER-2 and HER-3 or with HER-2 and HER-4. HRG inhibited the growth of cells with a high ratio of HER-2:HER-3, whereas HRG stimulated the growth of cells with low levels of the two receptors. In cells that express only HER-2 and HER-4, HRG stimulated the growth of cells that expressed HER-4 independent of HER-2 levels. Anti-HER-2 antibodies inhibited the growth of transfectants with high levels of HER-2 expression independent of HER-3 or HER-4 expression. In ovarian cancer cells that express all three receptors, the relative levels of HER-2 and HER-3 appear to determine the response to HRG. Taken together, these studies support the concept that the level of HER-2 expression can modulate response to HRG, determining whether the response is stimulatory or inhibitory. In contrast, agonistic antibodies that bind to HER-2 alone inhibit anchorage-independent growth but fail to mimic HRG's ability to stimulate growth of cells with low HER-2: HER-3 ratios.
authors.affiliation: Division of Medicine, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: F
authors.initials: F
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: X F
authors.initials: XF
authors.lastname: Le
authors.forename: C
authors.initials: C
authors.lastname: Boyer
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.forename: R C
authors.initials: RC
authors.lastname: Bast
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D029742:Caenorhabditis elegans Proteins; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology; D005260:Female; D015801:Helminth Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D020890:Neuregulin-1 / Q000494:pharmacology*; D010051:Ovarian Neoplasms; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000502:physiology*; D066247:Receptor, ErbB-4; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D029742:Caenorhabditis elegans Proteins; D066246:ErbB Receptors; D015801:Helminth Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C079744:her-1 protein, C elegans; C587689:ERBB4 protein, human