Overexpression of HER-2/neu in uterine serous papillary cancer.
OBJECTIVE
Uterine serous papillary carcinoma (USPC) is a highly aggressive variant of endometrial cancer and histologically similar to high-grade ovarian cancer. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistology in approximately 25% of ovarian cancers. In this study, we have evaluated the expression of HER-2/neu in several fresh, established, paraffin-embedded, fixed USPCs. In addition, we have tested the sensitivity of USPC cells to Herceptin treatment.


METHODS
Ten consecutive USPC specimens were assessed by immunohistochemistry for the intensity of expression of HER-2/neu. In addition, three USPC cell lines were analyzed for expression of HER-2/neu by flow cytometry as well as for sensitivity to Herceptin-mediated, complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and inhibition of cell proliferation.


RESULTS
Eight of 10 (80%) of the USPCs assessed immunohistochemically for the intensity of expression of HER-2/neu stained heavily for HER-2/neu (2+ to 3+). Fresh and established primary USPC cell lines were found to express significantly more HER-2/neu receptor by flow cytometry (on the average, 10-fold greater) when compared with HER-2/neu-positive primary or established breast and ovarian cancer cell lines (P < 0.001). Importantly, although these USPC cell lines were resistant to chemotherapy in vivo and to natural killer- and complement-mediated cytotoxicity in vitro, they were found to be highly sensitive to Herceptin-mediated ADCC. USPC cell proliferation was also inhibited by Herceptin. A significant enhancement of ADCC was demonstrated when effector cells were exposed to low doses of IL-2 in vitro. Physiological concentrations of human serum IgG did not inhibit Herceptin-mediated ADCC against USPC.


CONCLUSIONS
On the basis of these findings and previous reports showing a positive in vivo correlation between efficacy of Herceptin therapy and the level of HER-2/neu overexpression by tumor cells, we propose that Herceptin might be a novel and attractive therapeutic strategy in patients harboring chemotherapy-resistant, recurrent, or metastatic USPC.
Santin
Alessandro D
AD
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas, Little Rock 72205-7199, USA.
Bellone
Stefania
S
Gokden
Murat
M
Palmieri
Michela
M
Dunn
Donna
D
Agha
Jamshed
J
Roman
Juan J
JJ
Hutchins
Laura
L
Pecorelli
Sergio
S
O'Brien
Timothy
T
Cannon
Martin J
MJ
Parham
Groesbeck P
GP
D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D018283:Cystadenocarcinoma, Papillary / Q000378:metabolism / Q000473:pathology*; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D000069283:Rituximab; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000069283:Rituximab; D000068878:Trastuzumab