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[Cancer Research 61, 2420-2423, March 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Overexpression of HER-2 in Ovarian Carcinomas1

Ingegerd Hellström2, Gary Goodman, Janice Pullman, Yi Yang and Karl Erik Hellström

Program in Tumor Immunology, Pacific Northwest Research Institute [I. H., J. P., Y. Y., K. E. H.], and Swedish Hospital and Medical Center, Tumor Institute [G. G.], Seattle, Washington 98122


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. Shown by immunohistology, <25% of newly diagnosed ovarian carcinomas express the HER-2 protein. However, now we report that this protein was expressed in all 20 tumor cell lines derived from stage III and IV ovarian cancers as well as in tumor cells harvested from patients with malignant ascites and in tumor samples taken at a second surgery, suggesting that cells with excess expression may have a selective growth advantage. HER-2-positive ovarian carcinoma cells were shown to be sensitive to antibody-dependent cellular cytotoxicity, and their in vitro proliferation was inhibited by anti-HER-2 MAb Herceptin. We postulate, therefore, that therapy which targets HER-2 may be more efficacious in patients with ovarian carcinoma than indicated by the commonly low expression of HER-2 in tumors removed at the time of primary surgery.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The HER-2 (c-erbB2) proto-oncogene encodes a transmembrane receptor protein of Mr 185,000, which is structurally related to the epidermal growth factor receptor (1 , 2) . It is overexpressed in approximately one-third of primary breast carcinomas, by immunohistology (3) , and HER-2-positive breast cancers have a poorer prognosis than cancers not overexpressing this gene (2 , 3) . MAbs3 to HER-2 can inhibit the proliferation of tumor cells that overexpress this gene (4) , mediate antibody-dependent cellular cytotoxicity, and have antitumor activity in nude mice (5 , 6) . Importantly, a humanized MAb, Herceptin, has beneficial therapeutic effects in patients with strongly HER-2-positive primary breast carcinomas, particularly when combined with chemotherapeutic drugs (7 , 8) . According to immunohistology, at most 25% of primary ovarian carcinomas express the HER-2-encoded receptor, and, unlike breast cancer, it is controversial to what extent HER-2 amplification and protein overexpression correlates with prognosis (9 , 10) . It has, however, been reported that HER-2 expression is more frequent in ovarian carcinomas relapsing after chemotherapy (11) . We now show that tumor lines established in vitro from ovarian carcinomas, as well as ovarian carcinoma cells harvested from malignant ascites, frequently overexpress the Mr 185,000 HER-2 protein at their surfaces, suggesting that cells expressing this protein have a selective growth advantage over HER-2-negative cells. This finding suggests that patients with ovarian cancer may benefit from treatment with anti-HER-2 MAb plus chemotherapeutic drugs, both at an advanced stage (when the majority of tumor cells express HER-2) and at an earlier time, to eliminate the potentially more malignant HER-2-positive tumor cells.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Establishment of Cell Cultures.
Tumor samples (carcinomas of the ovary, breast, lung, etc.) were obtained from Swedish Hospital Medical Center and the Virginia Mason Hospital in Seattle as surgical biopsies or malignant effusions (ascites or pleural effusions). The cell lines that were used were established in our former laboratory at Bristol-Myers Squibb Pharmaceutical Research Institute in Seattle or at the Pacific Northwest Research Institute. The ovarian carcinoma line OVCAR-3 was obtained from the American Type Culture Collection (HTB161). This commonly used ovarian carcinoma line was chosen because it was isolated from a malignant effusion and is resistant to clinically relevant doses of Adriamycin, melphalan, and cisplatin (according to the American Type Culture Collection catalogue).

Tumor cells were grown in Iscove’s modified Dulbecco’s medium (Life Technologies, Inc., Grand Island, NY) with 20% fetal bovine serum (Atlanta Biological, Atlanta, GA), containing 1% penicillin/streptomycin (Life Technologies, Inc.), 20 mg/l bovine pituitary extract (Life Technologies, Inc.), 1% L-glutamine, and 5 pg/ml of bovine insulin. Culture bottles were incubated at 37°C in 5% CO2 in air atmosphere.

We studied 20 ovarian carcinoma lines, some of which had been established by in vitro culturing over 3–4 weeks and others over a much longer period of time. These lines commonly grew in the form of cell clusters (islands) which became confluent. For comparison, six breast carcinoma lines, three cervical carcinoma lines, two non-small cell lung carcinoma lines, three colon carcinoma lines, one pancreas carcinoma line, and one endometrial carcinoma line (all established in our laboratory) were included. In addition, we studied two B cell lines, Ramos and T5I, as well as normal PBLs for cell surface expression of HER-2.

FACS Analysis.
A PE-labeled anti-HER-2/neu (mouse IgG1) MAb was purchased from Becton Dickinson Immunocytometry Systems (San Jose, CA) and used for most of our studies. For comparison, we also used the clinically marketed anti-HER-2 MAb Herceptin (Genentech, CA). This is an IgG1{kappa} that contains human framework regions with the complementary-determining regions of a murine MAb and binds to the Mr 185,000 extracellular determinant of HER-2. As a control in the direct-staining experiments, we used PE-labeled mouse IgG1 (Beckman-Coulter, Miami, FL).

For staining by PE-labeled MAbs, target cells (500,000/MAb tested) were incubated with 20 µl of diluted MAb/sample for 30 min at 4°C in the dark, the supernatants removed by centrifugation, and then target cells were resuspended in PBS containing 2% fetal calf serum (FACS medium). After addition of 700-1000 µl of HBSS, the samples were analyzed by FACS using a Coulter Epics C FACS and the Coulter Epics x L2 software program. In experiments using Herceptin, a goat antihuman F(ab) (2) immunoglobulin was used, which had been conjugated with PE (BioSource International, Camarillo, CA). The chimeric anti-CD20 MAb Rituximab (Rituxan) was used as a control for Herceptin.

Tests for ADCC.
Tests were carried out as previously described (12) , labeling target cells with 51Cr and exposing them for 4 h to PBLs from one healthy donor/experiment and the antiHER-2 MAb Herceptin. The release of 51Cr from the target cells was measured as evidence of tumor cell lysis (cytotoxicity). Controls included the incubation of target cells alone or with either lymphocytes or MAb separately. Rituxan was used as a control MAb, and serum from a healthy human donor provided another control. ADCC was calculated as the percentage of killing of target cells observed with MAb plus effector cells, as compared with target cells being incubated alone.

Cell Proliferation Assay.
Cells from ovarian carcinoma lines OVCAR-3 and 3730 were plated at 2500 or 5000 cells/well in V-bottomed plates with various concentrations of Herceptin on day 0, using Rituxan as a control. On day 3, cells were pulsed with [H3] thymidine (1 µCi/well) for 6 h and then placed in a -20°C freezer for 1 h. After thawing at room temperature, cells were harvested using a Packard Filtermate Harvester Unifilter-96. Samples were incubated in 5 ml of Ready Safe liquid scintillation mixture (Beckman, Fullerton, CA), and radioactivity was determined by using a ß counter. Rituxan was used as a control MAb. Results are expressed as the percentage of inhibition [(untreated - treated/untreated x 100] with eight replicates/group.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
HER-2 Expression on Cells from Ovarian Carcinoma.
We first studied whether cultured cell lines established from biopsies of human ovarian carcinoma, as well as from malignant ascites, expressed HER-2 as detectable by FACS. The findings are summarized in Table 1Citation . Twenty ovarian carcinoma lines tested expressed HER-2 in >=14% of their cells, and 15 of the lines expressed HER-2 in >50% of the cells. Cells from neither of two B cell lines (Ramos and T5I) expressed HER-2 and neither did PBLs (data not shown). Cell lines established from several other tumors were also studied. More than 14% HER-2-positive cells were seen in two of six breast carcinoma lines, in three of three cervical carcinoma lines, in two of three colon carcinoma lines, and two of two lung carcinoma lines. The highest reactivity (73–91% and 72–81%) was found in cervical and lung carcinomas, respectively. Twelve tumors were also studied using Herceptin for indirect staining. The percentage of cells stained was only slightly lower than with the PE-labeled MAb. This is illustrated in Fig. 1Citation where both PE-labeled MAb and Herceptin stained most of the cells from OVCAR-3 without any clear difference between the two. As shown in Fig. 1ECitation , there was no staining of the T51 B lymphoma line, which was used as a control; cells from this line were stained by Rituxan (data not shown). As indicated in Table 1Citation , six experiments were performed in which Rituxan was used as a control to Herceptin in indirect staining assays with ovarian carcinoma samples. No significant binding was detected in any of these experiments.


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  		Table 1 Binding of PE-labeled anti-HER-2 MAb, Herceptin, to cultured cells from ovarian carcinoma

 


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  		Fig. 1. FACS analysis of ovarian carcinoma cells exposed to PE-labeled antiHER-2 MAb (Becton Dickinson) or Herceptin. Data with either of the two antiHER-2 MAbs are in solid black, and controls are in white. OVCAR-3 cells were used for experiments in A and B, demonstrating similar binding with the two different antiHER-2 MAbs. C, data with cultured cells from patient 11OV, whereas freshly harvested cells from ascites were used in D. E, cells from the B lymphoma line T51 were not stained by antiHER-2 MAb.

 
The high expression in cultured cells from ovarian carcinomas is in contrast to the much lower level of expression in biopsies from such tumors when studied by immunohistology, using the accepted criteria for classifying tumors as HER-2-positive or-negative; these experiments were performed at a large clinical laboratory (Dynacare), which is responsible for the evaluation of samples from various tumors (mostly carcinomas of the breast and ovary) for the expression of HER-2. All five primary ovarian carcinomas (3729, 3907, 4007, 4020, and 11OV) were then negative (referred to as "0% stained") for expression of the HER-2 receptor at the cell membrane, although carcinoma 3907 was described to have "scattered cells with cytoplasmic staining." In contrast, as shown in Table 1Citation , cell lines established from each of these tumors displayed high expression of HER-2 (>70% of the cells positive by FACS). It is also noteworthy that essentially all cells from either of two freshly harvested malignant effusions (11 OV and 50 OV) were HER-2 positive (79% and 93%, respectively); one of these tumors (11 OV) was negative for HER-2, according to immunohistology at the time of primary surgery. Fig. 1Citation shows FACS data with directly stained cells from freshly harvested cells from the 11 OV effusion (Fig. 1D)Citation , as well as for cells established in culture from such an effusion (Fig. 1C)Citation . Samples from an additional patient with ovarian carcinoma were tested by immunohistology (Oncotech, Irvine, CA) at the time of primary surgery and ~1 year later at debulking of relapsed tumor. Although her original tumor was negative (0% positive cells), the sample harvested after the patient had undergone chemotherapy and had a temporary, complete remission, had 70% cells with ++ staining.

HER-2-Positive Ovarian Carcinoma Cells Can Be Inhibited by AntiHER-2 MAb in Vitro and Are Targets for ADCC.
Three experiments were performed to investigate whether the proliferation of HER-2-positive ovarian carcinoma cells from either of two different lines, H3730 or OVCAR-3, can be inhibited by the antiHER-2 MAb Herceptin, as compared with Rituxan, which was used as control. Data presented in Table 2Citation show this to be the case, i.e., that these ovarian cancer lines behave similarly to HER-2-positive breast carcinomas (5) . Likewise, OVCAR-3 cells were killed by Herceptin but not by Rituxan (Fig. 2)Citation or by serum from a healthy human donor (data not shown) when combined with PBLs to mediate ADCC. Although the level of cytotoxicity seen in the presence of the PBLs and either culture medium or control antibody was high, it significantly increased (P < 0.01) at all three effector:target cell ratios tested in the presence of Herceptin. This experiment was repeated three times with similar results. Although only one ovarian carcinoma line was tested for sensitivity of ADCC, the data indicate that there is no fundamental difference between HER-2-positive ovarian and breast carcinomas.


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  		Table 2 Inhibition of 3Thymidine uptake by ovarian carcinoma cells grown in the presence of Herceptin

 


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  		Fig. 2. ADCC mediated by Herceptin (2 µg/ml) against 51Cr-labeled cells from ovarian carcinoma line OVCAR-3 (5000 cells/sample), as measured in combination with (Ficoll-Hypaque; separated) PBLs from a healthy, allogeneic donor in a 4-h assay, using three different effector:target cell ratios. The figure shows the percentage of target cell lysis (Bars, SD.) in an experiment performed with three replicates/point. No lysis was seen with Herceptin alone. Rituxan (2 µg/ml) was used as a control MAb.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
We have demonstrated that all of the 20 cell lines established from ovarian carcinomas consistently express the HER-2 oncoprotein at their surface, as detectable by FACS, and that in 75% of the lines, more than 50% of the cells were positive. This was also true for cell lines established from five primary ovarian carcinomas that were HER-2-negative according to standard immunohistological analysis. Furthermore, we show that cells harvested from malignant ascites of two patients and studied immediately strongly expressed HER-2, despite the fact that a biopsy, which was obtained from one of the original tumors, was HER-2-negative. Likewise, immunohistological studies on two different biopsies from an ovarian carcinoma patient demonstrated a shift from negativity to positivity when the tumor had relapsed after chemotherapy. We do not know whether the original tumors contained small fractions of HER-2-positive cells that were selected, e.g., in response to chemotherapy, or whether such cells appeared during tumor progression; and we neither know whether it is the overexpression of HER-2 per se that gives ovarian carcinoma cells a selective advantage. The use of techniques that are more sensitive than those presently applied when routinely evaluating HER-2 expression in tumors should be helpful in this regard. It is noteworthy that studies performed with the fluorescent in situ hybridization technique detected amplification of the HER-2 gene among 10 of 14 Stage III carcinomas removed at primary surgery (13) .

We conclude that overexpression of the extracellular domain of HER-2 is common as ovarian carcinomas progress. Because HER-2-positive ovarian carcinoma cells are sensitive to ADCC, and their in vitro growth can be inhibited by Herceptin, we postulate that antiHER-2 MAb can have beneficial effects in patients with ovarian carcinoma, including many of those who are negative according to routinely applied immunohistology on tumors removed at primary surgery. In view of the experience in breast carcinoma (6, 7, 8) , the postulated therapeutic effects are likely to significantly increase if the MAb were given with chemotherapeutic drugs. A tumor vaccine inducing antibodies and/or T cell immunity to HER-2 epitopes may ultimately provide the best means to prevent the emergence of HER-2-positive cells.


   ACKNOWLEDGMENTS
 
We thank Dr. J. A. Ledbetter for discussions.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by Special Program of Research Excellence Program Grant CA-98-008 from NIH to the Fred Hutchinson Cancer Research Center, subcontracted to I. H. at Pacific Northwest Research Institute for support of its Project No. 2. Back

2 To whom requests for reprints should be addressed, at Program in Tumor Immunology, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. Back

3 The abbreviations used are: PBL, peripheral blood lymphocyte; MAb, monoclonal antibody; FACS, flow cytometry; PE, phycoerythrin; ADCC, antibody-dependent cellular cytotoxicity; Back

Received 10/19/00. Accepted 1/31/01.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Coussens L., Yang-Feng T. L., Liao Y-C., Chen E., Gray A., McGrath J., Seeburg P. H., Libermann T. A., Schlessinger J., Francke U., Levinson A., Ullrich A. Tyrosin kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science (Washington DC), 230: 1132-1139, 1985.[Abstract/Free Full Text]
  2. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A., et al Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science (Washington DC), 244: 707-712, 1989.[Abstract/Free Full Text]
  3. Press M. F., Pike M. C., Chazin V. R., Hung G., Udove J. A., Markowicz M., Danyluk J., Godolphin W., Sliwkowski M., Akita R., Paterson M. C., Slamon D. J. Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. Cancer Res., 53: 4960-4970, 1993.[Abstract/Free Full Text]
  4. Hudziak R. M., Lewis G. D., Winget M., Fendly B. M., Shepard H. M., Ullrich A. p185 HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell. Biol., 9: 1165-1172, 1989.[Abstract/Free Full Text]
  5. Hotaling T. E., Reitz B., Wolfgang-Kimball D., Bauer K., Fox J. A. The humanized antiHER2 antibody rhuMab HER2 mediates antibody dependent cell-mediated cytotoxicity via Fc{gamma}RIII. Proc. Annu. Meet. Am. Assoc. Cancer Res., 37: 471 1996.
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