Biomedical subjects

A Berchuck

Publications and source records attributed to A Berchuck.

At least 91 records · Page 5Linked to original sources

PubMed1995

Loss of heterozygosity on chromosome 17q11-21 in cancers of women who have both breast and ovarian cancer.

OBJECTIVE: Our purpose was to determine the frequency of allele loss in the region of the BRCA1 gene in cancers of women who have both breast and ovarian cancer. STUDY DESIGN: Four polymorphic microsatellite markers on chromosome 17q11-21 were examined by the polymerase chain reaction in deoxyribonucleic acid from paraffin blocks of normal tissues, breast cancers, and ovarian cancers in 24 women who had primary cancers in both sites. RESULTS: Loss of heterozygosity was seen in one or more markers on chromosome 17q11-21 in 46% of breast cancers and 78% of ovarian cancers. In 38% of cases allele loss was seen in both cancers, and in all these cases the same allele was lost in both cancers. Significantly younger ages at diagnosis of both breast and ovarian cancer were noted among cases with allele loss in both cancers compared with cases in which allele loss was found only in the ovarian cancer (p < 0.05). CONCLUSIONS: Because cases in which 17q11-21 allele loss was seen in both cancers had a young age of onset and the same allele was always deleted in both cancers, hereditary alterations in BRCA1 may play a role in this subset. The older age of onset in cases in which allele loss was seen only in the ovarian cancer suggests that the development of these cancers is not related to an inherited defect in BRCA1.

Alleles↗

PubMed1995

Chemotherapy-induced apoptosis in epithelial ovarian cancers.

OBJECTIVE: To determine whether chemotherapy drugs elicit programmed cell death (apoptosis) in ovarian cancer cells. METHODS: Monolayers of immortalized ovarian cancer cell lines and primary ovarian cancer cells obtained from ascites were grown in the presence of cisplatin, 4-hydroxyperoxy-cyclophosphamide (the active metabolite of cyclophosphamide) or paclitaxel. Next, DNA was extracted from the cells and subjected to electrophoresis to determine if DNA laddering characteristic of apoptosis was present. RESULTS: In three of six immortalized cell lines (OVCA 420, 429, and 433), apoptosis was not seen in response to any of the three drugs. In contrast, in OVCAR-3 and OVCA 432, DNA laddering consistent with apoptosis was observed in response to all three drugs. In the DOV 13 cell line, apoptosis was seen only with 4-hydroxyperoxycyclophosphamide. Among three primary ovarian cancers, cisplatin elicited apoptosis in one case. Both cell lines with mutant p53 genes (OVCAR-3 and OVCA 432) underwent apoptosis in response to all three drugs, whereas among three cell lines known to have normal p53 genes, one underwent apoptosis in response to 4-hydroxyperoxycyclophosphamide and two were unaffected. CONCLUSION: Ovarian cancer cell death in response to commonly used chemotherapeutic drugs involves the induction of a genetically programmed sequence of events (apoptosis) rather than simply necrosis.

Apoptosis↗

PubMed1995

Mutational analysis of the estrogen-receptor gene in endometrial carcinoma.

OBJECTIVE: To determine whether mutation in the DNA of the estrogen-receptor gene occurs in endometrial cancer. METHODS: Polymerase chain reaction amplification and single-stranded conformation polymorphism analysis of the entire coding region (exons 1-8) of the human estrogen-receptor gene, as well as an untranslated region (exon I*) in the gene, were performed on genomic DNA extracted from 56 snap-frozen endometrial cancers. All cancers demonstrating mobility shifts on single-stranded conformation polymorphism suggestive of DNA sequence alteration were subjected to definitive DNA sequencing of the relevant portion of the estrogen-receptor gene. RESULTS: In addition to detecting a frequent, previously described polymorphism in exon 1, single-stranded conformation polymorphism analysis of the 56 endometrial cancers identified seven cancers with mobility shifts. Three cancers shifted in exon 3, one cancer each shifted in exons 4 and 7, and two shifted in exon 8. Deoxyribonucleic acid sequencing revealed sequence alterations in all seven cases demonstrating mobility shifts. In six of these seven cases, these alterations were consistent with infrequent silent polymorphisms; in the seventh cancer, the sequence alteration proved to be a somatic missense mutation at codon 537 in the region of the estrogen-receptor gene encoding the hormone-binding domain of the receptor protein. CONCLUSION: The infrequent DNA mutation in the estrogen-receptor gene is unlikely to account for the variation in estrogen-receptor expression observed in endometrial cancer.

Adult↗

PubMed1995

Relationship between race and interval to treatment in endometrial cancer.

OBJECTIVE: To determine whether the poor prognosis of black women with endometrial adenocarcinoma is due to racial differences in the interval between the onset of abnormal uterine bleeding and hysterectomy. METHODS: Clinical records of all 219 patients (176 white, 39 black, four other) who underwent surgical treatment of endometrial cancer during 1990-1993 at our institution were reviewed to obtain information regarding clinicopathologic features. In addition, the interval between the onset of abnormal uterine bleeding and hysterectomy was noted. RESULTS: Compared with white patients, black women with endometrial cancer had a significantly higher incidence of unfavorable features, including non-endometrioid histology (38 versus 12%), stage III or IV disease (51 versus 19%), grade 3 differentiation (49 versus 18%), and poor survival (P = .003). There was no significant difference in the median interval from onset of abnormal uterine bleeding to hysterectomy between blacks (11.1 weeks) and whites (13.7 weeks), nor was the interval to treatment related to stage, grade, histologic type, myometrial invasion, or survival. In contrast, patients with a history of hormone use had a longer median interval from the onset of abnormal bleeding to treatment compared with patients who had not used hormones (19 versus 10 weeks) (P < .01), and hormone use was associated with favorable clinicopathologic features and survival. Although black women were less likely to have used hormones than white women (13 versus 44%) (P < .001), racial differences in stage, grade, and survival persisted after correcting for hormone use. CONCLUSION: This study confirms that black women with endometrial cancer have a poorer outcome than white women; however, this does not appear to be due to a difference in the interval from onset of abnormal uterine bleeding to hysterectomy.

Adenocarcinoma↗

PubMed1995

Distribution of integrin cell adhesion molecules in endometrial cancer.

Integrins are ubiquitous cell adhesion molecules that are involved in maintaining normal tissue morphology and have been implicated in the behavior of certain malignancies. We examined the expression of nine integrin subunits in 38 endometrial adenocarcinomas using immunohistochemistry. The pattern of integrin expression in the cancers was compared with that seen in the endometrium of 20 normal cycling women and 7 postmenopausal women. Integrin expression was correlated with grade, stage, nodal status, depth of invasion, steroid receptor status, and histological pattern. In endometrial cancers there was an inverse relationship between the number of integrins expressed and histological grade (P = 0.011). Of the normally expressed, constitutive endometrial epithelial integrin subunits (alpha 2, alpha 3, alpha 6, and beta 4), the least frequently seen in the cancers was the alpha 3 subunit (44.7%) and the most frequently found was alpha 6 (81.6%). The alpha 5 beta 1 integrin, a fibronectin receptor normally found only on endometrial stromal cells, was seen in 17.8% of cases of these epithelial cancers. In addition, a significant association was found between the loss of the alpha 2 beta 1 integrin and the presence of lymph node metastases (P < 0.001). These data suggest that a decline in integrin expression occurs more frequently in poorly differentiated endometrial cancers and that the loss of specific integrins may be associated with metastatic nodal spread.

Adenocarcinoma↗

PubMed1995

Biomarkers in the ovary.

Alterations in specific oncogenes and tumor suppressor genes that serve as surrogate markers of malignant transformation have been identified in ovarian cancers. Overexpression of the HER-2/neu oncogene occurs in approximately 30% of breast and ovarian cancers. In most studies, HER-2/neu overexpression has correlated with poor survival. Although mutation of the K-ras oncogene has been found in some mucinous ovarian cancers, mutations in this gene appear to be more common in borderline ovarian tumors. Amplification of c-myc occurs in approximately 30% of ovarian cancers and is more frequently seen in serous cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 50% of Stage III/IV and 15% of Stage I/II ovarian cancers. Most p53 mutations in ovarian cancers are transitions, which suggests that they arise spontaneously rather than due to exogenous carcinogens. In contrast to the acquired genetic alterations described above that are a feature of sporadic ovarian cancers, a small fraction of epithelial ovarian cancers arise due to inherited genetic defects. Recently, the BRCA1 tumor suppressor gene on chromosome 17q was identified and shown to be responsible for some cases of hereditary breast and ovarian cancer. Families in which mutations in this gene exist are usually characterized by early age of disease onset. Presently, it remains unclear what fraction of hereditary ovarian cancers are due to BRCA1 mutations.

Biomarkers, Tumor↗

PubMed1994

Transforming growth factor-beta inhibits proliferation of human ovarian cancer cells obtained from ascites.

BACKGROUND: Previously, the authors found that immortalized ovarian cancer cell lines generally were resistant to the growth inhibitory effect of transforming growth factor-beta and frequently had lost the ability to produce or activate this growth factor. In this study, the authors examined whether early passage epithelial ovarian cancer cells obtained from ascites are growth-inhibited by or produce transforming growth factor-beta. METHODS: Ovarian cancer cells were purified from ascites by percoll gradient density centrifugation, and inflammatory cells were removed using anti-CD45 antibody. The effect of transforming growth factor-beta on the proliferation of ovarian cancer cells was assessed using the thymidine incorporation assay. Immunohistochemical staining for transforming growth factor-beta 1 and beta 2 also was performed in these cells. RESULTS: Transforming growth factor-beta (10 ng/ml) significantly inhibited [3H]thymidine incorporation in 19 of 20 (95%) primary ovarian cancers (P < 0.05). In cases in which significant inhibition was seen, the mean thymidine incorporation was 33 plus or minus 28% of control values. In addition, there was no difference in dose-dependent inhibition of proliferation between ovarian cancer cells and normal ovarian epithelial cells. Eleven of 18 ovarian cancers (61%) were found to express immunohistochemically detectable transforming growth factor-beta, but immunostaining was not observed in 39% of cases. CONCLUSIONS: Although most primary ovarian cancer cells remain sensitive to the growth-inhibitory effect of transforming growth factor-beta, loss of production may interrupt the transforming growth factor-beta autocrine inhibitory loop and play a role in the development of some ovarian cancers.

Ascites↗

PubMed1994

Multivariable analysis of DNA ploidy, p53, and HER-2/neu as prognostic factors in endometrial cancer.

BACKGROUND: Several molecular-genetic alterations in endometrial cancers, including aneuploidy and aberrant expression of p53 and HER-2/neu, have been associated with poor prognosis. To determine the importance of molecular-genetic factors relative to more traditional surgical-pathologic prognostic factors, a multivariable analysis was performed. METHODS: Immunohistochemical staining for p53, HER-2/neu, estrogen receptor, progesterone receptor, and epidermal growth factor receptor was performed on frozen sections from 100 primary endometrial cancers. DNA ploidy was determined using computerized image analysis of Feulgen-stained touch preparations. In addition, information regarding surgical-pathologic features of the cancers was obtained. Univariable analysis was performed followed by multivariable analysis using Cox's proportional hazards model to identify variables predictive of poor prognosis. RESULTS: With univariable analysis, race, histologic type, stage, grade, myometrial invasion, estrogen receptor, progesterone receptor, ploidy, p53 and HER-2/neu were predictive of the presence of persistent or recurrent disease. In the multivariable analysis, only International Federation of Gynecology and Obstetrics stage (P = 0.005), grade (P = 0.005), myometrial invasion (P = 0.024), and ploidy (P = 0.028) were significant. CONCLUSIONS: Among molecular-genetic prognostic factors, DNA ploidy was the most strongly predictive of persistent or recurrent disease.

Aged↗

PubMed1994

OVX1 as a marker for early stage endometrial carcinoma.

BACKGROUND: Endometrial carcinoma is generally diagnosed only after the onset of postmenopausal bleeding. Although most patients with Stage I disease can be cured, the prognosis worsens significantly when the tumor is no longer confined to the uterine corpus. Serum CA 125 is elevated in only 10-20% cases of Stage I and II endometrial carcinoma. A serum tumor marker that can detect early stage endometrial cancer might aid in management of the disease. METHODS: An OVX1 double-determinant radioimmunoassay was used to detect an epitope on a high-molecular-weight mucinlike glycoprotein found in the sera of 45 patients with endometrial cancer. RESULTS: Apparently healthy persons had serum OVX1 antigen levels of 2.23 plus or minus 2.48 U/ml (mean +/- standard deviation). Elevated levels of OVX1 antigen (> 7.2 U/ml) were found in 5% of 184 healthy persons and in 64% of 45 patients with endometrial cancer. OVX1 antigen was elevated in 64% of 36 patients with Stage I, 50% of 2 patients with Stage II, 60% of 5 patients with Stage III, and each of 2 patients with Stage IV endometrial cancer, but only 8.6% of 58 patients with endometriosis. Elevation of serum OVX1 was found more frequently in patients with deep myometrial invasion and with poorly differentiated tumors (P < 0.01). CONCLUSIONS: The OVX1 antigen deserves further evaluation as a marker for early detection of endometrial cancers and as a prognostic factor for women with apparent early stage disease.

Antigens, Neoplasm↗

PubMed1994

Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression.

BACKGROUND: The p185c-erbB-2 growth factor receptor protein tyrosine kinase (PTK) is overexpressed in one third of human breast cancer patients and indicates a poor prognosis in these patients. Protein tyrosine phosphatases (PTPs) may balance PTK activity as part of normal growth-regulation pathways. PTP1B is an intracellular PTP that is involved in linkage between signal transduction pathways and may interface with inappropriate PTK activity in transformed cells. PURPOSE: The aim of this study was to determine if PTP1B is overexpressed in human mammary tumors and to determine if such overexpression is associated with the overexpression of the p185c-erbB-2 receptor PTK. METHODS: Our samples were frozen sections from 29 human mammary tumors (19 pure infiltrating, two pure intraductal, and eight combined intraductal and infiltrating) and nine sections from normal breast tissue. The sections were immunohistochemically stained for PTP1B and p185c-erbB-2, and the results were analyzed statistically for association between overexpression of the two proteins. Northern blot analysis was used to assess if PTP1B overexpression was coincident with increased transcription of the PTP1B gene. RESULTS: Overexpression of the PTP1B protein was observed in 72.4% of the tumor sections compared with normal epithelium, with maximal expression occurring in 37.9% of the tumors. All of the tumor subtypes, including the pure intraductal lesions, overexpressed PTP1B. Statistical analyses demonstrated a significant association between PTP1B overexpression and breast cancer (P < .038) and between the overexpression of PTP1B and the overexpression of p185c-erbB-2 (P < .006). PTP1B messenger RNA steady-state transcription was consistently increased in tumors versus normal tissues. CONCLUSIONS: PTP1B overexpression is a common phenotypic manifestation in human breast cancers and is associated with over-expression of p185c-erbB-2. Steady-state PTP1B transcription is increased in tumor tissue. IMPLICATIONS: Further studies are needed to determine if PTP1B overexpression balances or augments PTK activity. PTP1B overexpression might also be evaluated as a clinical prognostic factor in human breast cancers.

Blotting, Northern↗

PubMed1994

Overexpression of p53 is not a feature of benign and early-stage borderline epithelial ovarian tumors.

Since overexpression of mutant p53 protein is a common feature of invasive epithelial ovarian cancers, we investigated whether overexpression of the p53 tumor suppressor gene product occurs in benign and borderline epithelial ovarian tumors. Immunohistochemical staining for p53 was performed in frozen samples of 17 benign tumors and in 49 borderline tumors (4 frozen, 45 paraffin embedded). Overexpression of p53 was observed in 0/17 (0%) benign ovarian tumors and 2/49 (4%) borderline tumors. Overexpression of p53 in borderline tumors was only seen in advanced stage cases; overexpression was seen in 2/8 (25%) stage III cases, but not in any of 41 stage I/II cases. In conclusion, overexpression of p53 is not a feature of benign epithelial ovarian tumors or early-stage borderline ovarian tumors. Similar to invasive epithelial ovarian cancers, however, a fraction of metastatic borderline tumors also overexpress p53.

Adult↗

PubMed1994

Transfection of ovarian cancer cells with tumor necrosis factor-alpha (TNF-alpha) antisense mRNA abolishes the proliferative response to interleukin-1 (IL-1) but not TNF-alpha.

Recombinant interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can induce endogenous TNF-alpha mRNA expression and stimulate proliferation of epithelial ovarian cancer cells. In a previous report, proliferation induced by either cytokine could be partially blocked by soluble TNF-alpha receptor or by neutralizing antibodies against TNF-alpha. In the present study, we have transfected the ovarian cancer cell line OVCA 432 with vectors that contain the TNF-alpha gene in the antisense or sense orientation. Antisense-transfected cells showed a 4.5- to 26-fold reduction in IL-1-induced TNF-alpha secretion. Similarly, the stimulation of [3H]thymidine incorporation by IL-1 but not by TNF-alpha was blocked by TNF-alpha antisense transfection. These results are consistent with a model in which the macrophage-derived cytokines IL-1 and TNF-alpha might stimulate endogenous production of TNF-alpha that in turn could stimulate proliferation of ovarian cancer cells by autocrine growth regulation.

Cell Division↗

PubMed1994

5-day methotrexate for women with metastatic gestational trophoblastic disease.

The objective of this study was to analyze the toxicity and the efficacy of single-agent 5-day methotrexate for women with metastatic gestational trophoblastic disease. The study is a retrospective analysis of 52 patients who received repetitive 5-day cycles of intramuscular methotrexate as primary therapy for metastatic trophoblastic disease between 1975 and 1990. The majority of patients were low-risk by both clinical and World Health Organization prognostic index score criteria. Sixty percent achieved primary remission with a median of 3 cycles of single-agent methotrexate. Therapy was changed because of toxicity and drug-resistance by hCG criteria in 11 (21%) and 10 (19%) patients, respectively. Pretherapy hCG > 10,000 mIU/ml was associated with the development of drug-resistance. Remission was achieved in all patients, with only 2 (4%) requiring multiagent therapy. The use of repetitive 5-day cycles of methotrexate is efficacious therapy of low-risk metastatic trophoblastic disease. Future studies are needed to define a cost-effective and minimally toxic therapy that retains a high primary remission rate in these patients.

Analysis of Variance↗

PubMed1994

Differential expression of the 67-kD laminin receptor and 31-kD human laminin-binding protein in human ovarian carcinomas.

The expression of the 67-kD laminin receptor (67LR) and the 31-kD human laminin-binding protein (HLBP31), two proteins involved in cancer cell laminin interaction, was evaluated on 30 ovarian cancer specimens. Expression of the 67LR was increased (up to 2.5-fold, in 87% of the patients), while HLBP31 expression was downregulated in cancer cells compared with the normal tissue, as detected by northern blotting and immunohistochemistry. The immunohistochemical study demonstrated that the 67LR was significantly overexpressed (P < 0.05) in the group of patients whose cytoreductive surgery was suboptimal, and those with poor clinical outcome. No correlation was observed between HLBP31 expression and clinicopathological features. Increased expression of the 67LR appears to correlate with the invasive phenotype of ovarian cancer cells and suggests a role of the latter in ovarian cancer invasion.

Carrier Proteins↗

PubMed1994

Overexpression of the tyrosine phosphatase PTP1B is associated with human ovarian carcinomas.

OBJECTIVE: Our purpose was to determine whether protein tyrosine phosphatase 1B is overexpressed in ovarian cancers, possibly altering the balance of intracellular tyrosine phosphorylation. STUDY DESIGN: The expression of protein tyrosine phosphatase 1B was assayed in frozen sections from 54 human ovarian carcinomas and seven normal ovaries by immunochemical staining with monoclonal antibody AE4-2J, which is specific for protein tyrosine phosphatase 1B. The expression of protein tyrosine phosphatase 1B-specific messenger ribonucleic acid in tumors was determined by Northern analysis. The results were analyzed statistically by means of Fisher's exact test. RESULTS: Minimal staining was observed in normal ovarian epithelium. In contrast, 43 of 54 (79.6%) tumors displayed increased protein tyrosine phosphatase 1B expression, which is statistically associated with malignancy. Overexpression was associated with the expression of the p185c-erbB-2, p170EGFR, and p165mCSFR growth factor receptor protein tyrosine kinases. Protein tyrosine phosphatase 1B messenger ribonucleic acid expression was inconsistently increased in tumor cells. CONCLUSION: Increased expression of protein tyrosine phosphatase 1B in ovarian cancers that also express protein tyrosine kinases suggests that protein tyrosine phosphatase 1B may play a role in the growth regulation of ovarian cancers.

Female↗

PubMed1994

The p53 tumor suppressor gene frequently is altered in gynecologic cancers.

Mutation of the p53 tumor suppressor gene, often accompanied by overexpression of mutant p53 protein, is the most frequent molecular genetic event described thus far in human cancers. In adenocarcinomas of the ovary and endometrium, p53 overexpression is seen in approximately 10% to 15% of early and 40% to 50% of advanced cancers. Similar to many other types of human cancers, ovarian and endometrial cancers that overexpress p53 protein contain mutations in conserved regions of the p53 gene. These mutations are predominantly transitions, which suggests that they arise spontaneously rather than being caused by carcinogen exposure. Alteration of the p53 gene does not appear to be a feature of endometrial hyperplasias or benign or borderline ovarian tumors. Although mutation and overexpression of p53 rarely occur in cancers of the cervix, vulva, and vagina, it has been shown that human papillomavirus E6 oncoproteins bind to and inactivate p53 protein. Studies of the p53 gene have begun to provide insight into the molecular pathogenesis of gynecologic cancers.

Adenocarcinoma↗

PubMed1994

Mutations of the E-cadherin gene in human gynecologic cancers.

Expression of the E-cadherin cell adhesion molecule is reduced in several types of human carcinomas, and the protein serves as an invasion suppressor in vitro. To determine if mutations of the E-cadherin gene (on chromosome 16q22) contribute to epithelial tumorigenesis, 135 carcinomas of the endometrium and ovary were examined for alterations in the E-cadherin coding region. Four mutations were identified: one somatic nonsense and one somatic missense mutation, both with retention of the wild-type alleles, and two missense mutations with somatic loss of heterozygosity in the tumour tissue. These data support the classification of E-cadherin as a human tumour suppressor gene.

Alleles↗

PubMed1994

Determination of proliferation index with MIB-1 in advanced ovarian cancer using quantitative image analysis.

A new monoclonal antibody, MIB-1, reacts with the same epitope recognized by Ki-67. The authors investigated the feasibility of using image analysis to quantitate the MIB-1 staining (proliferation index [PI]) of epithelial ovarian cancers. The PI was determined in 50 advanced-stage primary ovarian cancers. Paraffin sections were immunostained with the MIB-1 monoclonal antibody, and the PI was calculated using a CAS 200 image analyzer. Among 36 stage III ovarian carcinomas, the median PI was 15.1%, compared with 18.9% in 14 stage IV cancers (P = .47). Based on exploratory methods, a cutoff point of 7% best dichotomized these patients into two prognostic groups. Of 39 patients whose cancers had a high MIB-1 expression (> or = 7%), the median survival was 16.5 months, which differed significantly (P = .01) from the median survival of 33.2 months observed in the 11 patients whose tumors demonstrated low MIB-1 expression (< 7%). Using MIB-1 as a binary variable, a strong correlation was found between overexpression of c-erbB-2 (2+ and 3+) and MIB-1 > or = 7% (P = .001). No relationship was found between PI and histologic grade. Further studies are warranted to investigate the relationship between MIB-1, PI expression, and other known clinicopathologic and genetic features of early- and late-stage ovarian cancer.

Antibodies, Monoclonal↗