G. Rodriguez

Overexpression of HER-2/neu in endometrial cancer is associated with advanced stage disease.

Prior studies have shown that overexpression of HER-2/ neu occurs in one third of breast and ovarian cancers and that overexpression is associated with poor prognosis. We used a monoclonal antibody to assess immunohistochemically the level of HER-2/ neu expression in normal and malignant endometrium. In 24 normal endometrial samples light to moderate (1+ to 2+) staining for HER-2/ neu was seen in the glands, and there was no variation in intensity of staining during the menstrual cycle. Among 95 endometrial adenocarcinomas, nine (9%) were found to have heavier staining for HER-2/ neu than was seen in normal endometrium (3+). High expression of HER-2/ neu was found in 27% of patients with metastatic disease compared with 4% of patients with disease confined to the uterus (p neu expression also was associated with absence of estrogen receptor (p neu overexpression in endometrial cancer.

Regulation of growth of normal ovarian epithelial cells and ovarian cancer cell lines by transforming growth factor-β

OBJECTIVE The purpose of this study was to study the role of transforming growth factor-beta in regulation of proliferation of normal and malignant ovarian epithelial cells. STUDY DESIGN We examined production of and responsiveness to transforming growth factor-beta in primary monolayer cultures of epithelial cells from five normal human ovaries and in five ovarian cancer cell lines. RESULTS In normal ovarian epithelial cells, proliferation always was inhibited by transforming growth factor-beta (greater than 40%) (p less than 0.01). Among the cancer cell lines, proliferation of one was markedly inhibited (greater than 95%) (p less than 0.01), two were only modestly inhibited (15% to 20%) (p less than 0.05), and two were unaffected. In addition, we found that all of the normal ovarian epithelial cells and four of five ovarian cancer cell lines produce transforming growth factor-beta ribonucleic acid and protein. CONCLUSIONS These data suggest that transforming growth factor-beta may act as an autocrine growth inhibitory factor for normal ovarian epithelium in vivo. Because most of the ovarian cancer cell lines are relatively resistant to the growth inhibitory effect of transforming growth factor-beta and because one cell line does not produce transforming growth factor-beta, it is possible that loss of the transforming growth factor-beta pathway may play a role in the development of some ovarian cancers.

Ovarian Adenocarcinomas in the Laying Hen and Women Share Similar Alterations in p53, ras, and HER-2/neu

We examined alterations in the p53 tumor suppressor gene and the ras and HER-2/neu oncogenes in chicken ovarian cancers to determine if these tumors have genetic alterations similar to those in human ovarian adenocarcinomas. Mutations in the p53 tumor suppressor gene and the H-ras and K-ras oncogenes were assessed by direct sequencing in 172 ovarian cancers obtained from 4-year-old birds enrolled at age 2 in two separate 2-year chemoprevention trials. Birds in trial B had approximately twice as many lifetime ovulations as those in trial A. Immunohistochemical staining for the HER-2/neu oncogene was done on a subset of avian ovarian and oviductal adenocarcinomas. Alterations in p53 were detected in 48% of chicken ovarian cancers. Incidence of p53 alterations varied according to the number of lifetime ovulations, ranging from 14% in trial A to 96% in trial B (P < 0.01). No mutations were seen in H-ras, and only 2 of 172 (1.2%) tumors had K-ras mutations. Significant HER-2/neu staining was noted in 10 of 19 ovarian adenocarcinomas but in only 1 of 17 oviductal adenocarcinomas. Similar to human ovarian cancers, p53 alterations are common in chicken ovarian adenocarcinomas and correlate with the number of lifetime ovulations. Ras mutations are rare, similar to high-grade human ovarian cancers. HER-2/neu overexpression is common and may represent a marker to exclude an oviductal origin in cancers involving both the ovary and oviduct.

Reduction of Ovarian and Oviductal Cancers in Calorie-Restricted Laying Chickens

Epithelial ovarian cancer (OVAC) remains a highly lethal malignancy. It is a leading cause of cancer deaths among women in the United States causing more deaths than all other gynecologic malignancies combined. The pathogenesis of OVAC is not completely understood, but the process of repeated ovulation is believed to lead to genetic damage in the ovarian epithelium. As part of a prospective trial designed to evaluate OVAC chemopreventive strategies using the chicken model, caloric restriction (55% less energy) was used to inhibit ovulation in groups of hens receiving chemopreventives, thereby minimizing the impact of ovulation on the incidence of reproductive tract cancer. A separate group of chickens was maintained concurrently in the same environment, and managed similarly, except that caloric intake was not restricted. Among birds not receiving chemopreventive agents, we compared caloric versus noncaloric restricted birds to determine the relations between calorie restriction and risk of developing adenocarcinoma of the reproductive tract. Mortality in the calorie-restricted group was almost half that of those on full feed. Calorie-restricted chickens maintained body weights averaging 1.423 kg compared with the full-fed birds at 1.892 kg. Ovulation rate varied with the full-fed group producing 64% more eggs than the calorie-restricted group. Total reproductive cancers occurred in 57 (33.3%) birds for the full-fed group and 26 (10.3%) birds for the calorie-restricted group. On the basis of histopathology, 45 (26.3%) birds in the full-fed group had ovarian adenocarcinoma compared with 16 (6.3%) birds in the calorie-restricted group. Calorie restriction in laying hens resulted in a near five-fold reduction in OVAC. Cancer Prev Res; 4(4); 562–7. ©2011 AACR.

Regulation of growth of normal ovarian epithelium and ovarian cancer cell lines by transforming growth factor-β

OBJECTIVE: The purpose of this study was to study the role of transforming growth factor-(3 in regulation of proliferation of normal and malignant ovarian epithelial cells. STUDY DESIGN: We examined production of and responsiveness to transforming growth factor-(3 in primary monolayer cultures of epithelial cells from five normal human ovaries and in five ovarian cancer cell lines. RESULTS: In normal ovarian epithelial cells, proliferation always was inhibited by transforming growth factor-(3 (>40%) (p 95%) (p < 0.01), two were only modestly inhibited (15% to 20%) (p < 0.05), and two were unaffected. In addition, we found that all of the normal ovarian epithelial cells and four of five ovarian cancer cell lines produce transforming growth factor-(3 ribonucleic acid and protein. CONCLUSIONS: These data suggest that transforming growth factor-(3 may act as an autocrine growth inhibitory factor for normal ovarian epithelium in vivo. Because most of the ovarian cancer cell lines are relatively resistant to the growth inhibitory effect of transforming growth factor-[3 and because one cell line does not produce transforming growth factor-(3, it is possible that loss of the transforming growth factor-(3 pathway may playa role in the development of some ovarian cancers. (AM J OSSTET GVNECOL 1992;166:676-84.)

Alternating weekly chemotherapy with etoposide-methotrexatedactinomycin/cyclophosphamide-vincristine for high-risk gestational trophoblastic disease

Objective: To evaluate the response rate and toxicity of alternating weekly therapy with etoposide-methotrexatedactinomycin/cyclophosphamide-vincristine for women with high-risk gestational trophoblastic disease. Methods: Twenty-two women with gestational trophoblastic disease received 126 cycles of the study regimen. Response was evaluated by serial hCG monitoring. Toxicity was assessed using standard criteria. Results: Six women (27%) were treated for primary therapy and 16 (73%) for secondary therapy. The median prognostic index score was 11 (range 7-19). Only 23% of the patients and 11% of the 126 treatment cycles had grade neutropenia, despite the heavily pretreated patient population. Only 2% of the cycles were associated with neutropenic sepsis or required platelet transfusions. Nonhematologic toxicity was modest. Among 16 women who received chemotherapy alone, there were 11 (69%) complete and three (19%) partial responses. When adjuvant therapies are included, the overall complete and partial response rates were 77 and 14%, respectively. Six (35%) of 17 complete responders developed recurrences. Five patients with partial response or relapse were salvaged with additional therapy. Fifteen of the 22 patients (68%) have sustained remissions. Conclusion: The regimen of alternating weekly etoposidemethotrexate- dactinomycin/cyclophosphamide-vincristine is effective and well-tolerated chemotherapy for patients with high-risk gestational trophoblastic disease.

Overexpression of HER-2/neu in endometrial cancer is associated with advanced stage disease

Prior studies have shown that overexpression of HER-2/neu occurs in one third of breast and ovarian cancers and that overexpression is associated with poor prognosis. We used a monoclonal antibody to assess immunohistochemically the level of HER-2/neu expression in normal and malignant endometrium. In 24 normal endometrial samples light to moderate (1+ to 2+) staining for HER-2/neu was seen in the glands, and there was no variation in intensity of staining during the menstrual cycle. Among 95 endometrial adenocarcinomas, nine (9%) were found to have heavier staining for HER-2/neu than was seen in normal endometrium (3+). High expression of HER-2/neu was found in 27% of patients with metastatic disease compared with 4% of patients with disease confined to the uterus (p less than 0.005). High HER-2/neu expression also was associated with absence of estrogen receptor (p less than 0.005) and with increased mortality from cancer. Further studies are needed to determine the significance of HER-2/neu overexpression in endometrial cancer.

Expression of epidermal growth factor receptor and HER‐2/neu in normal and neoplastic cervix, vulva, and vagina

Monoclonal antibodies were used to localize immunohisto-chemically epidermal growth factor receptor and HER-2/neu in normal and neoplastic frozen tissue samples from the lower genital tract of women. In squamous epithelia of the cervix, vulva, and vagina, epidermal growth factor receptor and HER-2/neu both were expressed most strongly by basal keratinocytes. Expression of both of these cell surface molecules decreased as cells underwent differentiation toward the mucosal surface. In contrast, both epidermal growth factor receptor and HER-2/neu were expressed throughout the entire thickness of the epithelium by undifferentiated squamous cells in squamous metaplasia, raised condyloma, and carcinoma in situ. In 34 squamous cancers of the cervix, vulva, and vagina, all malignant cells were found to have moderate to heavy staining for epidermal growth factor receptor. Staining of 33 of these cancers for HER-2/neu was light, although one patient who presented with distant metastases had heavy staining for HER-2/neu. These data suggest that although overexpression of HER-2/neu in squamous cancers of the lower genital tract is a rare event, it may be associated with aggressive biologic behavior.